bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024‒01‒28
sixty-one papers selected by
Viktor Korolchuk, Newcastle University
  1. p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson-Gilford progeria syndrome.
  2. Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models.
  3. Role of lysosome in healing neurological disorders by nano-bioengineering.
  4. The mTORC2 signaling network: targets and cross-talks.
  5. Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches.
  6. ADP-Ribosylation Factor-Interacting Protein 2 Acts as a Novel Regulator of Mitophagy and Autophagy in Podocytes in Diabetic Nephropathy.
  7. Neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis in C. elegans.
  8. Lithium treatment rescues dysfunctional autophagy in the cell models of Tay-Sachs disease.
  9. High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice.
  10. Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases.
  11. Xenophagy receptors Optn and p62 and autophagy modulator Dram1 independently promote the zebrafish host defense against Mycobacterium marinum.
  12. Endothelial Cell Aging and Autophagy Dysregulation.
  13. Cadmium toxicity and autophagy: a review.
  14. NOP14-mediated ribosome biogenesis is required for mTORC2 activation and predicts rapamycin sensitivity.
  15. Deficiency of diacylglycerol Kinase ζ promotes Beclin1-mediated autophagy via the mTOR/TFEB signaling pathway: Relevance to maladaptive cardiac hypertrophy.
  16. 3-Hydroxy-3-methylglutaryl-CoA synthase 2 facilitates erectile dysfunction via inhibiting autophagy by enhancing the mammalian target of rapamycin pathway in type 1 diabetic mellitus rats.
  17. Role of Tumor Cell Intrinsic and Host Autophagy in Cancer.
  18. ATG14 targets lipid droplets and acts as an autophagic receptor for syntaxin18-regulated lipid droplet turnover.
  19. A NOVEL MTORC2-AKT-ROS AXIS TRIGGERS MITOFISSION and MITOPHAGY-ASSOCIATED EXECUTION of COLORECTAL CANCER CELLS UPON DRUG-INDUCED ACTIVATION of MUTANT KRAS.
  20. Selective autophagy in cancer: mechanisms, therapeutic implications, and future perspectives.
  21. TFEB and TFE3 cooperate in regulating inorganic arsenic-induced autophagy-lysosome impairment and immuno-dysfunction in primary dendritic cells.
  22. Beclin-1 haploinsufficiency ameliorates high fat diet-induced myocardial injury via inhibiting alternative mitophagy.
  23. Inhibition of VHL by VH298 Accelerates Pexophagy by Activation of HIF-1α in HeLa Cells.
  24. The Dual Role of Sulforaphane-Induced Cellular Stress-A Systems Biological Study.
  25. Dynamic organelle changes and autophagic processes in lily pollen germination.
  26. Heparin-binding hemagglutinin of Mycobacterium tuberculosis inhibits autophagy via TLR4 and drives M2 polarization in macrophages.
  27. Mitochondrial dynamics and mitochondrial autophagy: Molecular structure, orchestrating mechanism and related disorders.
  28. Crosstalk between autophagy and metabolism: implications for cell survival in acute myeloid leukemia.
  29. Role of ATG7-dependent non-autophagic pathway in angiogenesis.
  30. Mechanisms regulating the intracellular trafficking and release of CLN5 and CTSD.
  31. Biomimetic Nanomedicine Targeting Orchestrated Metabolism Coupled with Regulatory Factors to Disrupt the Metabolic Plasticity of Breast Cancer.
  32. The potential influence of melatonin on mitochondrial quality control: a review.
  33. Psychological stress induces hair regenerative disorders through corticotropin-releasing hormone-mediated autophagy inhibition.
  34. Methionine sulfoxide reductase 2 regulates Cvt autophagic pathway by altering the stability of Atg19 and Ape1 in Saccharomyces cerevisiae.
  35. PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity.
  36. Treatment with sodium butyrate induces autophagy resulting in therapeutic benefits for spinocerebellar ataxia type 3.
  37. Fluctuation of lysosomal protein degradation in neural stem cells of the postnatal mouse brain.
  38. Mechanistic Target of Rapamycin Kinase is a Common Convergent Pathway to Renal Neoplasia: A Contemporary Review.
  39. A pH imbalance is linked to autophagic dysregulation of inner ear hair cells in Atp6v1ba-deficient zebrafish.
  40. The skin photoprotective effect of trilinolein: Induction of cellular autophagy via the AMPK-mTOR signaling pathway.
  41. Interaction of Tau with Kinesin-1: Effect of Kinesin-1 Heavy Chain Elimination on Autophagy-Mediated Mutant Tau Degradation.
  42. Mobilization of cholesterol induces the transition from quiescence to growth in Caenorhabditis elegans through steroid hormone and mTOR signaling.
  43. Larixyl acetate, a TRPC6 inhibitor, attenuates pressure overload‑induced heart failure in mice.
  44. ALS' Perfect Storm: C9orf72-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis.
  45. Shared structural features of Miro binding control mitochondrial homeostasis.
  46. Contribution of Autophagy to Cellular Iron Homeostasis and Stress Adaptation in Alternaria alternata.
  47. A pathogenic variant in the FLCN gene presenting with pure dementia: is autophagy at the intersection between neurodegeneration and cancer?
  48. Glial senescence enhances α-synuclein pathology owing to its insufficient clearance caused by autophagy dysfunction.
  49. Autophagy Markers Are Altered in Alzheimer's Disease, Dementia with Lewy Bodies and Frontotemporal Dementia.
  50. Eliminating the invading extracellular and intracellular FnBp+ bacteria from respiratory epithelial cells by autophagy mediated through FnBp-Fn-Integrin α5β1 axis.
  51. Valsa mali effector Vm_04797 interacts with adaptor protein MdAP-2β to manipulate host autophagy.
  52. Mitochondrial translocation of TFEB regulates complex I and inflammation.
  53. Epigallocatechin-3-Gallate and Genistein for Decreasing Gut Dysbiosis, Inhibiting Inflammasomes, and Aiding Autophagy in Alzheimer's Disease.
  54. LUBAC promotes angiogenesis and lung tumorigenesis by ubiquitinating and antagonizing autophagic degradation of HIF1α.
  55. Autophagy and Apoptosis in Rabies Virus Replication.
  56. Rapid turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation.
  57. Rapamycin-sensitive mechanisms confine the growth of fission yeast below the temperatures detrimental to cell physiology.
  58. Regulation of Benzo[a]pyrene-Induced Hepatic Lipid Accumulation through CYP1B1-Induced mTOR-Mediated Lipophagy.
  59. Methyl vinyl ketone and its analogs covalently modify PI3K and alter physiological functions by inhibiting PI3K signaling.
  60. MicroRNA-141-3p reduces pulmonary hypoxia/reoxygenation injury through suppression of Beclin-1-dependent autophagy.
  61. Effect of ATG8 or SAC1 deficiency on the cell proliferation and lifespan of the long-lived PMT1 deficiency yeast cells.
  1. Nat Cell Biol. 2024 Jan 24.
    p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson-Gilford progeria syndrome.
    Sung Min Son, So Jung Park, Sophia Y Breusegem, Delphine Larrieu, David C Rubinsztein.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth, metabolism and autophagy. Multiple pathways modulate mTORC1 in response to nutrients. Here we describe that nucleus-cytoplasmic shuttling of p300/EP300 regulates mTORC1 activity in response to amino acid or glucose levels. Depletion of these nutrients causes cytoplasm-to-nucleus relocalization of p300 that decreases acetylation of the mTORC1 component raptor, thereby reducing mTORC1 activity and activating autophagy. This is mediated by AMP-activated protein kinase-dependent phosphorylation of p300 at serine 89. Nutrient addition to starved cells results in protein phosphatase 2A-dependent dephosphorylation of nuclear p300, enabling its CRM1-dependent export to the cytoplasm to mediate mTORC1 reactivation. p300 shuttling regulates mTORC1 in most cell types and occurs in response to altered nutrients in diverse mouse tissues. Interestingly, p300 cytoplasm-nucleus shuttling is altered in cells from patients with Hutchinson-Gilford progeria syndrome. p300 mislocalization by the disease-causing protein, progerin, activates mTORC1 and inhibits autophagy, phenotypes that are normalized by modulating p300 shuttling. These results reveal how nutrients regulate mTORC1, a cytoplasmic complex, by shuttling its positive regulator p300 in and out of the nucleus, and how this pathway is misregulated in Hutchinson-Gilford progeria syndrome, causing mTORC1 hyperactivation and defective autophagy.
    DOI:  https://doi.org/10.1038/s41556-023-01338-y
  2. Mol Neurodegener. 2024 Jan 25. 19(1): 12
    Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models.
    Aitor Martinez, Alvaro Sanchez-Martinez, Jake T Pickering, Madeleine J Twyning, Ana Terriente-Felix, Po-Lin Chen, Chun-Hong Chen, Alexander J Whitworth.
      BACKGROUND: Mitochondrial dysfunction and toxic protein aggregates have been shown to be key features in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease (PD). Functional analysis of genes linked to PD have revealed that the E3 ligase Parkin and the mitochondrial kinase PINK1 are important factors for mitochondrial quality control. PINK1 phosphorylates and activates Parkin, which in turn ubiquitinates mitochondrial proteins priming them and the mitochondrion itself for degradation. However, it is unclear whether dysregulated mitochondrial degradation or the toxic build-up of certain Parkin ubiquitin substrates is the driving pathophysiological mechanism leading to PD. The iron-sulphur cluster containing proteins CISD1 and CISD2 have been identified as major targets of Parkin in various proteomic studies.METHODS: We employed in vivo Drosophila and human cell culture models to study the role of CISD proteins in cell and tissue viability as well as aged-related neurodegeneration, specifically analysing aspects of mitophagy and autophagy using orthogonal assays.
    RESULTS: We show that the Drosophila homolog Cisd accumulates in Pink1 and parkin mutant flies, as well as during ageing. We observed that build-up of Cisd is particularly toxic in neurons, resulting in mitochondrial defects and Ser65-phospho-Ubiquitin accumulation. Age-related increase of Cisd blocks mitophagy and impairs autophagy flux. Importantly, reduction of Cisd levels upregulates mitophagy in vitro and in vivo, and ameliorates pathological phenotypes in locomotion, lifespan and neurodegeneration in Pink1/parkin mutant flies. In addition, we show that pharmacological inhibition of CISD1/2 by rosiglitazone and NL-1 induces mitophagy in human cells and ameliorates the defective phenotypes of Pink1/parkin mutants.
    CONCLUSION: Altogether, our studies indicate that Cisd accumulation during ageing and in Pink1/parkin mutants is a key driver of pathology by blocking mitophagy, and genetically and pharmacologically inhibiting CISD proteins may offer a potential target for therapeutic intervention.
    Keywords:  Ageing; Autophagy; CISD1; CISD2; Cisd; Mitochondria; Mitophagy; Neurodegeneration; PINK1; Parkin; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s13024-024-00701-3
  3. Front Neurosci. 2023 ;17 1331211
    Role of lysosome in healing neurological disorders by nano-bioengineering.
    Aiswarya Raj, Urmi Bandyopadhyay.
      Lysosomes primarily recognized as center for cellular 'garbage-disposing-unit', which has recently emerged as a crucial regulator of cellular metabolism. This organelle is a well-known vital player in the pathology including neurodegenerative disorders. In pathological context, removal of intracellular damaged misfolded proteins, organelles and aggregates are ensured by 'Autophagy' pathway, which initially recognizes, engulfs and seals the toxic cargo at the cytosolic environment. Thereafter the cell completes the task of encapsulated cargo elimination upon delivery of them to the terminal compartment - lysosome, which contains acid hydrolases, that are capable of degrading the abnormal protein-lipid-repertoire. The merge between inseparable 'Autophagy' and 'Lysosomal' pathways evolved into 'Autophagy-Lysosome Pathway (ALP)', through which cell ultimately degrades and recycles bio-materials for metabolic needs. Dysregulation of any of the steps of the multi-step ALP can contribute to the development and progression of disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Therefore, targeting differential steps of ALP or directly lysosomes using nano-bioengineering approaches holds great promise for therapeutic interventions. This review aims to explore the role of distal autophagy pathway and proximal lysosomal function, as cellular degradative and metabolic hubs, in healing neurological disorders and highlights the contributions of nano-bioengineering in this field. Despite multiple challenges, this review underscores the immense potential of integrating autophagy-lysosomal biology with nano-bioengineering to revolutionize the field and provide novel therapeutic avenues for tackling neurological-neurodegenerative-disorders.
    Keywords:  amino acid; autophagy; bioengineering; lysosome; nanotechnology; neurodegenerative disorder
    DOI:  https://doi.org/10.3389/fnins.2023.1331211
  4. Biochem J. 2024 Jan 25. 481(2): 45-91
    The mTORC2 signaling network: targets and cross-talks.
    Aparna Ragupathi, Christian Kim, Estela Jacinto.
      The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.
    Keywords:  Akt; SIN1; cell growth; mTOR; mTORC2; metabolism; rictor
    DOI:  https://doi.org/10.1042/BCJ20220325
  5. Front Cell Neurosci. 2023 ;17 1307636
    Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches.
    Saman Rashid, Maria Dimitriadi.
      Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by the depletion of the ubiquitously expressed survival motor neuron (SMN) protein. While the genetic cause of SMA has been well documented, the exact mechanism(s) by which SMN depletion results in disease progression remain elusive. A wide body of evidence has highlighted the involvement and dysregulation of autophagy in SMA. Autophagy is a highly conserved lysosomal degradation process which is necessary for cellular homeostasis; defects in the autophagic machinery have been linked with a wide range of neurodegenerative disorders, including amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. The pathway is particularly known to prevent neurodegeneration and has been suggested to act as a neuroprotective factor, thus presenting an attractive target for novel therapies for SMA patients. In this review, (a) we provide for the first time a comprehensive summary of the perturbations in the autophagic networks that characterize SMA development, (b) highlight the autophagic regulators which may play a key role in SMA pathogenesis and (c) propose decreased autophagic flux as the causative agent underlying the autophagic dysregulation observed in these patients.
    Keywords:  autophagic flux; autophagy; macroautophagy; mitophagy; spinal muscular atrophy
    DOI:  https://doi.org/10.3389/fncel.2023.1307636
  6. Antioxidants (Basel). 2024 Jan 08. pii: 81. [Epub ahead of print]13(1):
    ADP-Ribosylation Factor-Interacting Protein 2 Acts as a Novel Regulator of Mitophagy and Autophagy in Podocytes in Diabetic Nephropathy.
    Haihua Guo, Manuel Rogg, Julia Keller, Ann-Kathrin Scherzinger, Julia Jäckel, Charlotte Meyer, Alena Sammarco, Martin Helmstädter, Oliver Gorka, Olaf Groß, Christoph Schell, Wibke Bechtel-Walz.
      (1) Background: Differentiated podocytes are particularly vulnerable to oxidative stress and cellular waste products. The disease-related loss of postmitotic podocytes is a direct indicator of renal disease progression and aging. Podocytes use highly specific regulated networks of autophagy and endocytosis that counteract the increasing number of damaged protein aggregates and help maintain cellular homeostasis. Here, we demonstrate that ARFIP2 is a regulator of autophagy and mitophagy in podocytes both in vitro and in vivo. (2) Methods: In a recent molecular regulatory network analysis of mouse glomeruli, we identified ADP-ribosylation factor-interacting protein 2 (Arfip2), a cytoskeletal regulator and cofactor of ATG9-mediated autophagosome formation, to be differentially expressed with age. We generated an Arfip2-deficient immortalized podocyte cell line using the CRISPR/Cas technique to investigate the significance of Arfip2 for renal homeostasis in vitro. For the in vivo analyses of Arfip2 deficiency, we used a mouse model of Streptozotozin-induced type I diabetes and investigated physiological data and (patho)histological (ultra)structural modifications. (3) Results: ARFIP2 deficiency in immortalized human podocytes impedes autophagy. Beyond this, ARFIP2 deficiency in human podocytes interferes with ATG9A trafficking and the PINK1-Parkin pathway, leading to the compromised fission of mitochondria and short-term increase in mitochondrial respiration and induction of mitophagy. In diabetic mice, Arfip2 deficiency deteriorates autophagy and leads to foot process effacement, histopathological changes, and early albuminuria. (4) Conclusions: In summary, we show that ARFIP2 is a novel regulator of autophagy and mitochondrial homeostasis in podocytes by facilitating ATG9A trafficking during PINK1/Parkin-regulated mitophagy.
    Keywords:  ADP-ribosylation factor-interacting protein 2; Arfip2; CKD; autophagy; diabetes; mitophagy; podocyte
    DOI:  https://doi.org/10.3390/antiox13010081
  7. bioRxiv. 2024 Jan 04. pii: 2023.07.31.551399. [Epub ahead of print]
    Neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis in C. elegans.
    Shane K B Taylor, Jessica H Hartman, Bhagwati P Gupta.
      The conserved mesencephalic astrocyte-derived neurotrophic factor (MANF) protects dopaminergic neurons but also functions in several other tissues. Previously, we showed that Caenorhabditis elegans manf-1 null mutants have increased ER stress, dopaminergic neurodegeneration, protein aggregation, slower growth, and a reduced lifespan. The multiple requirements of MANF in different systems suggest its essential role in regulating cellular processes. However, how intracellular and extracellular MANF regulates broader cellular function remains unknown. Here, we report a novel mechanism of action for manf-1 that involves the autophagy transcription factor HLH-30/TFEB-mediated signaling to regulate lysosomal function and aging. We generated multiple transgenic strains overexpressing MANF-1 and found that animals had extended lifespan, reduced protein aggregation, and improved neuronal health. Using a fluorescently tagged MANF-1, we observed different tissue localization of MANF-1 depending on the ER retention signal. Further subcellular analysis showed that MANF-1 localizes within cells to the lysosomes. These findings were consistent with our transcriptomic studies and, together with analysis of autophagy regulators, demonstrate that MANF-1 regulates protein homeostasis through increased autophagy and lysosomal activity. Collectively, our findings establish MANF as a critical regulator of the stress response, proteostasis, and aging.
    DOI:  https://doi.org/10.1101/2023.07.31.551399
  8. Mol Genet Metab. 2024 Jan 11. pii: S1096-7192(24)00024-6. [Epub ahead of print]141(3): 108140
    Lithium treatment rescues dysfunctional autophagy in the cell models of Tay-Sachs disease.
    Hande Basirli, Melike Can, Tugce Sengul, Volkan Seyrantepe.
      Tay-Sachs disease is a rare lysosomal storage disorder (LSD) caused by a mutation in the HexA gene coding β-hexosaminidase A enzyme. The disruption of the HexA gene causes the accumulation of GM2 ganglioside resulting in progressive neurodegeneration in humans. Surprisingly, Hexa-/- mice did not show neurological phenotypes. Our group recently generated a murine model of Tay-Sachs disease exhibiting excessive GM2 accumulation and severe neuropathological abnormalities mimicking Tay-Sachs patients. Previously, we reported impaired autophagic flux in the brain of Hexa/-Neu3-/- mice. However, regulation of autophagic flux using inducers has not been clarified in Tay-Sachs disease cells. Here, we evaluated the effects of lithium treatment on dysfunctional autophagic flux using LC3 and p62 in the fibroblast and neuroglia of Hexa-/-Neu3-/- mice and Tay-Sachs patients. We discovered the clearance of accumulating autophagosomes, aggregate-prone metabolites, and GM2 ganglioside under lithium-induced conditions. Our data suggest that targeting autophagic flux with an autophagy inducer might be a rational therapeutic strategy for the treatment of Tay-Sachs disease.
    Keywords:  Autophagy; Autophagy inducer; Lysosomal storage disorder; Tay-Sachs disease; lithium
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108140
  9. Acta Pharm Sin B. 2024 Jan;14(1): 190-206
    High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice.
    Xiaojuan Chao, Mengwei Niu, Shaogui Wang, Xiaowen Ma, Xiao Yang, Hua Sun, Xujia Hu, Hua Wang, Li Zhang, Ruili Huang, Menghang Xia, Andrea Ballabio, Hartmut Jaeschke, Hong-Min Ni, Wen-Xing Ding.
      Macroautophagy (referred to as autophagy hereafter) is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles. Previous studies showed that autophagy protects against acetaminophen (APAP)-induced injury (AILI) via selective removal of damaged mitochondria and APAP protein adducts. The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes. In the present study, we showed that transcription factor EB (TFEB), a master transcription factor for lysosomal biogenesis, was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers. Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI, respectively. Mechanistically, overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2 (NRF2) activation to protect against AILI. We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists. Among these agonists, salinomycin, an anticoccidial and antibacterial agent, activated TFEB and protected against AILI in mice. In conclusion, genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.
    Keywords:  Autophagy; DILI; Drug screening; Hepatotoxicity; Lysosome; Mitochondria; Mitophagy; NRF2
    DOI:  https://doi.org/10.1016/j.apsb.2023.10.017
  10. Biology (Basel). 2024 Jan 07. pii: 34. [Epub ahead of print]13(1):
    Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases.
    Elisabet Uribe-Carretero, Verónica Rey, Jose Manuel Fuentes, Isaac Tamargo-Gómez.
      Lysosomes are the main organelles responsible for the degradation of macromolecules in eukaryotic cells. Beyond their fundamental role in degradation, lysosomes are involved in different physiological processes such as autophagy, nutrient sensing, and intracellular signaling. In some circumstances, lysosomal abnormalities underlie several human pathologies with different etiologies known as known as lysosomal storage disorders (LSDs). These disorders can result from deficiencies in primary lysosomal enzymes, dysfunction of lysosomal enzyme activators, alterations in modifiers that impact lysosomal function, or changes in membrane-associated proteins, among other factors. The clinical phenotype observed in affected patients hinges on the type and location of the accumulating substrate, influenced by genetic mutations and residual enzyme activity. In this context, the scientific community is dedicated to exploring potential therapeutic approaches, striving not only to extend lifespan but also to enhance the overall quality of life for individuals afflicted with LSDs. This review provides insights into lysosomal dysfunction from a molecular perspective, particularly in the context of human diseases, and highlights recent advancements and breakthroughs in this field.
    Keywords:  autophagosome; autophagy; genetic mutations; lysosomal storage disease; lysosome; therapeutic approaches
    DOI:  https://doi.org/10.3390/biology13010034
  11. Front Cell Infect Microbiol. 2023 ;13 1331818
    Xenophagy receptors Optn and p62 and autophagy modulator Dram1 independently promote the zebrafish host defense against Mycobacterium marinum.
    Jiajun Xie, Annemarie H Meijer.
      Anti-bacterial autophagy, also known as xenophagy, is a crucial innate immune process that helps maintain cellular homeostasis by targeting invading microbes. This defense pathway is widely studied in the context of infections with mycobacteria, the causative agents of human tuberculosis and tuberculosis-like disease in animal models. Our previous work in a zebrafish tuberculosis model showed that host defense against Mycobacterium marinum (Mm) is impaired by deficiencies in xenophagy receptors, optineurin (Optn) or sequestome 1 (p62), and Damage-regulated autophagy modulator 1 (Dram1). However, the interdependency of these receptors and their interaction with Dram1 remained unknown. In the present study, we used single and double knockout zebrafish lines in combination with overexpression experiments. We show that Optn and p62 can compensate for the loss of each other's function, as their overexpression restores the infection susceptibility of the mutant phenotypes. Similarly, Dram1 can compensate for deficiencies in Optn and p62, and, vice versa, Optn and p62 compensate for the loss of Dram1, indicating that these xenophagy receptors and Dram1 do not rely on each other for host defense against Mm. In agreement, Dram1 overexpression in optn/p62 double mutants restored the interaction of autophagosome marker Lc3 with Mm. Finally, optn/p62 double mutants displayed more severe infection susceptibility than the single mutants. Taken together, these results suggest that Optn and p62 do not function downstream of each other in the anti-mycobacterial xenophagy pathway, and that the Dram1-mediated defense against Mm infection does not rely on specific xenophagy receptors.
    Keywords:  Dram1; Mycobacterium; Optn; autophagy; innate immunity; p62; tuberculosis; xenophagy
    DOI:  https://doi.org/10.3389/fcimb.2023.1331818
  12. Cardiovasc Hematol Agents Med Chem. 2024 Jan 23.
    Endothelial Cell Aging and Autophagy Dysregulation.
    Basheer Abdullah Marzoog.
      Entropy is a natural process that affects all living cells, including senescence, an irreversible physiological process that impairs cell homeostasis. Age is a significant factor in disease development, and the pathogenesis of endothelial cell aging is multifactorial. Autophagy dysfunction accelerates endothelial cell aging and cell death, while autophagy preserves endothelial cell youthfulness through intracellular homeostasis and gene expression regulation. Sirt, mTORC1, and AMPK are youthfulness genes that induce autophagy by inhibiting mTOR and upregulating FIP200/Atg13/ULK1. Aged endothelial cells have decreased levels of Lamin B1, γH2AX, Ki67, BrdU, PCNA, and SA β-Gal. Maintaining healthy young endothelial cells can prevent most cardiovascular diseases. Autophagy targeting is a potential future therapeutic strategy to modify endothelial cell age and potentially slow or reverse the aging process. This article provides state-of-the-art research on the role of autophagy in endothelial cell aging. Hypothesizing that autophagy dysregulation is associated with early endothelial cell dysfunction and further clinical sequelae, including atherosclerosis formation, leading to various cardiovascular diseases.
    Keywords:  Aging; Autophagy; Longevity; Pathogenesis; Senolytics; Sirtuin; endothelial cell
    DOI:  https://doi.org/10.2174/0118715257275690231129101408
  13. Biometals. 2024 Jan 26.
    Cadmium toxicity and autophagy: a review.
    Yueting Shao, Liting Zheng, Yiguo Jiang.
      Cadmium (Cd) is an important environmental pollutant that poses a threat to human health and represents a critical component of air pollutants, food sources, and cigarette smoke. Cd is a known carcinogen and has toxic effects on the environment and various organs in humans. Heavy metals within an organism are difficult to biodegrade, and those that enter the respiratory tract are difficult to remove. Autophagy is a key mechanism for counteracting extracellular (microorganisms and foreign bodies) or intracellular (damaged organelles and proteins that cannot be degraded by the proteasome) stress and represents a self-protective mechanism for eukaryotes against heavy metal toxicity. Autophagy maintains cellular homeostasis by isolating and gathering information about foreign chemicals associated with other molecular events. However, autophagy may trigger cell death under certain pathological conditions, including cancer. Autophagy dysfunction is one of the main mechanisms underlying Cd-induced cytotoxicity. In this review, the toxic effects of Cd-induced autophagy on different human organ systems were evaluated, with a focus on hepatotoxicity, nephrotoxicity, respiratory toxicity, and neurotoxicity. This review also highlighted the classical molecular pathways of Cd-induced autophagy, including the ROS-dependent signaling pathways, endoplasmic reticulum (ER) stress pathway, Mammalian target of rapamycin (mTOR) pathway, Beclin-1 and Bcl-2 family, and recently identified molecules associated with Cd. Moreover, research directions for Cd toxicity regarding autophagic function were proposed. This review presents the latest theories to comprehensively reveal autophagy behavior in response to Cd toxicity and proposes novel potential autophagy-targeted prevention and treatment strategies for Cd toxicity and Cd-associated diseases in humans.
    Keywords:  Autophagy; Cadmium; Cell fate; Toxic mechanism
    DOI:  https://doi.org/10.1007/s10534-023-00581-y
  14. J Biol Chem. 2024 Jan 23. pii: S0021-9258(24)00057-7. [Epub ahead of print] 105681
    NOP14-mediated ribosome biogenesis is required for mTORC2 activation and predicts rapamycin sensitivity.
    Xiao Yan, Bo-Hua Kuang, Shengsuo Ma, Ruihua Wang, Jinzhong Lin, Yi-Xin Zeng, Xiaoduo Xie, Lin Feng.
      The mechanistic target of rapamycin (mTOR) forms two distinct complexes: rapamycin-sensitive mTOR complex 1 (mTORC1) and rapamycin-insensitive mTORC2. mTORC2 primarily regulates cell survival by phosphorylating Akt, though the upstream regulation of mTORC2 remains less well defined than that of mTORC1. In this study, we show that NOP14, a 40S ribosome biogenesis factor and a target of the mTORC1-S6K axis, plays an essential role in mTORC2 signaling. Knockdown of NOP14 led to mTORC2 inactivation and Akt destabilization. Conversely, overexpression of NOP14 stimulated mTORC2-Akt activation and enhanced cell proliferation. Fractionation and coimmunoprecipitation assays demonstrated that the mTORC2 complex was recruited to the rough endoplasmic reticulum (ER) through association with ER-bound ribosomes. In vivo, high levels of NOP14 correlated with poor prognosis in multiple cancer types. Notably, cancer cells with NOP14 high expression exhibit increased sensitivity to mTOR inhibitors, because the feedback activation of the PI3K-PDK1-Akt axis by mTORC1 inhibition was compensated by mTORC2 inhibition partly through NOP14 downregulation. In conclusion, our findings reveal a spatial regulation of mTORC2-Akt signaling and identify ribosome biogenesis as a potential biomarker for assessing rapalog response in cancer therapy.
    Keywords:  Akt; NOP14; mTORC2; rapalog; ribosome
    DOI:  https://doi.org/10.1016/j.jbc.2024.105681
  15. Int J Med Sci. 2024 ;21(3): 439-453
    Deficiency of diacylglycerol Kinase ζ promotes Beclin1-mediated autophagy via the mTOR/TFEB signaling pathway: Relevance to maladaptive cardiac hypertrophy.
    Yumei Liu, Han Zhang, Yaxian Lin, Peipei Qian, Yuan Yin, Ganglin Zou, Jinxin Zhang, Haining Zhang.
      The activation Gq protein-coupled receptors (GPCRs) is a crucial factor contributing to maladaptive cardiac hypertrophy, and dysregulation of autophagy is implicated in its prohypertrophic effects. Previous studies have shown that diacylglycerol kinase zeta (DGKζ) can suppress cardiac hypertrophy by inhibiting the diacylglycerol (DAG)-PKC pathway in response to mechanical strain or growth agonists such as endothelin-1 (ET-1). However, the involvement of DGKζ in autophagy regulation remains poorly understood. In this study, we aimed to investigate the role of DGKζ in autophagy regulation during maladaptive cardiac hypertrophy. We found that Beclin1-mediated autophagy was involved in the development of maladaptive cardiac hypertrophy and dysfunction in response to prohypertrophic challenges of transverse aortic constriction (TAC) or ET-1. Deficiency of DGKζ promoted Beclin1-mediated autophagy, aggravated adverse cardiac remodeling, and cardiac dysfunction, which could be ameliorated by genetic deletion of Beclin1 or TFEB. Mechanistically, the deficiency of DGKζ disrupted the activation of AKT/mTOR signaling, the association between mTOR and TFEB, and favored the nuclear translocation of TFEB from the cytoplasm, leading to enhanced activation of Beclin1-mediated autophagy through ULK1/Beclin1 signaling and TFEB-dependent Beclin1 transcription. Taken together, these results suggest that the mechanisms by which DGKζ alleviates pathological cardiac hypertrophy may involve the regulation of Beclin1-mediated autophagy through the mTOR/TFEB signaling pathway.
    Keywords:  Autophagy; Cardiac hypertrophy; DGKζ; TFEB
    DOI:  https://doi.org/10.7150/ijms.88134
  16. Andrology. 2024 Jan 25.
    3-Hydroxy-3-methylglutaryl-CoA synthase 2 facilitates erectile dysfunction via inhibiting autophagy by enhancing the mammalian target of rapamycin pathway in type 1 diabetic mellitus rats.
    Zhiqiang Dai, Yang Zeng, Xiao Tan, Tao Zhou, Xiong Li, Qingfu Deng.
      BACKGROUND: The relationship between erectile dysfunction (ED) and type 1 diabetes mellitus (T1DM) is currently a hot topic of medical research. It has been reported that autophagy plays a crucial role in causing erectile dysfunction in T1DM. Recent research has shown that mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) is strongly linked to the development of T1DM. However, the specific mechanism by which it regulates the erectile function is not yet fully understood.OBJECTIVES: To investigate whether HMGCS2 affects erectile function in type 1 diabetic rats by regulating autophagy in corpus cavernosum endothelial cells (CCECs).
    MATERIALS AND METHODS: First, the rat model of T1DM was established. Then, the ratio of maximum penile intracavernous pressure (ICPmax) and mean arterial pressure (MAP) was detected to assess the erectile function in various groups, and the protein expression of HMGCS2, mTOR and p-mTOR was evaluated by western blot (WB) and immunohistochemistry (IHC). To explore the relationship between HMGCS2 and the mTOR signaling pathway in T1DM ED rats, we silenced the expression of HMGCS2 and activated the mTOR signaling pathway with MHY1485 in CCECs and then assessed the expression of beclin1, P62, LC3, autophagosome, endothelial nitric oxide synthase (eNOS), phosphorylation of eNOS (p-eNOS), and nitric oxide (NO) to evaluate autophagy and the erectile function by reverse transcription quantitative polymerase chain reaction and western blot.
    RESULTS: The study conducted on T1DM ED rats showed that the expression of HMGCS2 was significantly increased, while the autophagy was suppressed. Additionally, the mTOR signaling pathway was highly activated. In contrast, when HMGCS2 was silenced in vitro, p-mTOR/mTOR was reduced, and autophagy was improved. These effects were accompanied by the enhanced activity of eNOS. Furthermore, when HMGCS2 was silenced and the mTOR signaling pathway was simultaneously activated, the results revealed a decrease in autophagy as well as a reduction in activity of eNOS in comparison to just silencing HMGCS2 alone.
    DISCUSSION AND CONCLUSION: HMGCS2 upregulation in T1DM rats inhibited autophagy and eNOS activity by activating the mTOR pathway and led to a decrease in the erectile function.
    Keywords:  HMGCS2; autophagy; erectile dysfunction; mTOR; type 1 diabetic mellitus
    DOI:  https://doi.org/10.1111/andr.13600
  17. Cold Spring Harb Perspect Med. 2024 Jan 22. pii: a041539. [Epub ahead of print]
    Role of Tumor Cell Intrinsic and Host Autophagy in Cancer.
    Jessie Yanxiang Guo, Eileen White.
      Macroautophagy (autophagy hereafter) is an intracellular nutrient scavenging pathway induced by starvation and other stressors whereby cellular components such as organelles are captured in double-membrane vesicles (autophagosomes), whereupon their contents are degraded through fusion with lysosomes. Two main purposes of autophagy are to recycle the intracellular breakdown products to sustain metabolism and survival during starvation and to eliminate damaged or excess cellular components to suppress inflammation and maintain homeostasis. In contrast to most normal cells and tissues in the fed state, tumor cells up-regulate autophagy to promote their growth, survival, and malignancy. This tumor-cell-autonomous autophagy supports elevated metabolic demand and suppresses tumoricidal activation of the innate and adaptive immune responses. Tumor-cell-nonautonomous (e.g., host) autophagy also supports tumor growth by maintaining essential tumor nutrients in the circulation and tumor microenvironment and by suppressing an antitumor immune response. In the setting of cancer therapy, autophagy is a resistance mechanism to chemotherapy, targeted therapy, and immunotherapy. Thus, tumor and host autophagy are protumorigenic and autophagy inhibition is being examined as a novel therapeutic approach to treat cancer.
    DOI:  https://doi.org/10.1101/cshperspect.a041539
  18. Nat Commun. 2024 Jan 20. 15(1): 631
    ATG14 targets lipid droplets and acts as an autophagic receptor for syntaxin18-regulated lipid droplet turnover.
    Zhen Yuan, Kun Cai, Jiajia Li, Ruifeng Chen, Fuhai Zhang, Xuan Tan, Yaming Jiu, Haishuang Chang, Bing Hu, Weiyi Zhang, Binbin Ding.
      Lipid droplets (LDs) are dynamic lipid storage organelles that can be degraded by autophagy machinery to release neutral lipids, a process called lipophagy. However, specific receptors and regulation mechanisms for lipophagy remain largely unknown. Here, we identify that ATG14, the core unit of the PI3KC3-C1 complex, also targets LD and acts as an autophagic receptor that facilitates LD degradation. A negative regulator, Syntaxin18 (STX18) binds ATG14, disrupting the ATG14-ATG8 family members interactions and subverting the PI3KC3-C1 complex formation. Knockdown of STX18 activates lipophagy dependent on ATG14 not only as the core unit of PI3KC3-C1 complex but also as the autophagic receptor, resulting in the degradation of LD-associated anti-viral protein Viperin. Furthermore, coronavirus M protein binds STX18 and subverts the STX18-ATG14 interaction to induce lipophagy and degrade Viperin, facilitating virus production. Altogether, our data provide a previously undescribed mechanism for additional roles of ATG14 in lipid metabolism and virus production.
    DOI:  https://doi.org/10.1038/s41467-024-44978-w
  19. Autophagy. 2024 Jan 23.
    A NOVEL MTORC2-AKT-ROS AXIS TRIGGERS MITOFISSION and MITOPHAGY-ASSOCIATED EXECUTION of COLORECTAL CANCER CELLS UPON DRUG-INDUCED ACTIVATION of MUTANT KRAS.
    Kartini Iskandar, Jonathan Foo, Angeline Qiu Xia Liew, Haiyuxin Zhu, Deepika Raman, Jayshree L Hirpara, Yan Yi Leong, Maria V Babak, Anna A Kirsanova, Anne-Sophie Armand, Franck Oury, Gregory Bellot, Shazib Pervaiz.
      RAS is one of the most commonly mutated oncogenes associated with multiple cancer hallmarks. Notably, RAS activation induces intracellular reactive oxygen species (ROS) generation, which we previously demonstrated as a trigger for autophagy-associated execution of mutant KRAS-expressing cancer cells. Here we report that drug (merodantoin; C1)-induced activation of mutant KRAS promotes phospho-AKT S473-dependent ROS-mediated S616 phosphorylation and mitochondrial localization of DNM1L/DRP1 (dynamin 1 like) and cleavage of the fusion-associated protein OPA1 (OPA1 mitochondrial dynamin like GTPase). Interestingly, accumulation of the outer mitochondrial membrane protein VDAC1 (voltage dependent anion channel 1) is observed in mutant KRAS-expressing cells upon exposure to C1. Conversely, silencing VDAC1 abolishes C1-induced mitophagy, and gene knockdown of either KRAS, AKT or DNM1L rescues ROS-dependent VDAC1 accumulation and stability, thus suggesting an axis of mutant active KRAS-phospho-AKT S473-ROS-DNM1L-VDAC1 in mitochondrial morphology change and cancer cell execution. Importantly, we identified MTOR (mechanistic target of rapamycin kinsase) complex 2 (MTORC2) as the upstream mediator of AKT phosphorylation at S473 in our model. Pharmacological or genetic inhibition of MTORC2 abrogated C1-induced phosphorylation of AKT S473, ROS generation and mitophagy induction, as well as rescued tumor colony forming ability and migratory capacity. Finally, increase in thermal stability of KRAS, AKT and DNM1L were observed upon exposure to C1 only in mutant KRAS-expressing cells. Taken together, our work has unraveled a novel mechanism of selective targeting of mutant KRAS-expressing cancers via MTORC2-mediated AKT activation and ROS-dependent mitofission, which could have potential therapeutic implications given the relative lack of direct RAS-targeting strategies in cancer.
    Keywords:  AKT; DNM1L; KRAS; MTORC2; ROS; mitofission
    DOI:  https://doi.org/10.1080/15548627.2024.2307224
  20. Mol Cancer. 2024 Jan 24. 23(1): 22
    Selective autophagy in cancer: mechanisms, therapeutic implications, and future perspectives.
    Jiaxi Liu, Yongya Wu, Sha Meng, Ping Xu, Shutong Li, Yong Li, Xiuying Hu, Liang Ouyang, Guan Wang.
      Eukaryotic cells engage in autophagy, an internal process of self-degradation through lysosomes. Autophagy can be classified as selective or non-selective depending on the way it chooses to degrade substrates. During the process of selective autophagy, damaged and/or redundant organelles like mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes, and lipid droplets are selectively recycled. Specific cargo is delivered to autophagosomes by specific receptors, isolated and engulfed. Selective autophagy dysfunction is closely linked with cancers, neurodegenerative diseases, metabolic disorders, heart failure, etc. Through reviewing latest research, this review summarized molecular markers and important signaling pathways for selective autophagy, and its significant role in cancers. Moreover, we conducted a comprehensive analysis of small-molecule compounds targeting selective autophagy for their potential application in anti-tumor therapy, elucidating the underlying mechanisms involved. This review aims to supply important scientific references and development directions for the biological mechanisms and drug discovery of anti-tumor targeting selective autophagy in the future.
    Keywords:  Cancer; Molecular mechanism; Selective autophagy; Small-molecule compounds; Targeted therapy
    DOI:  https://doi.org/10.1186/s12943-024-01934-y
  21. Cell Biol Toxicol. 2024 Jan 25. 40(1): 4
    TFEB and TFE3 cooperate in regulating inorganic arsenic-induced autophagy-lysosome impairment and immuno-dysfunction in primary dendritic cells.
    Guowei Xu, Huaguang Peng, Ran Yao, Yuqing Yang, Bing Li.
      Arsenic (As) is a prevalent and hazardous environmental toxicant associated with cancer and various health problems, which has been shown suppressive effects on dendritic cells (DCs). Autophagy is essential for the innate and adaptive immune responses of DCs, and the transcription factors TFEB and TFE3 are key regulators of autophagic and lysosomal target genes. However, the detrimental alterations of the autophagy-lysosome pathway in As-exposed DCs and the possible coordinating roles of TFEB and TFE3 in the immune dysfunction of this cell are less understood. In this paper, we found that As exposure significantly impaired lysosomal number, lysosomal acidic environment, and lysosomal membrane permeabilization, which might lead to blocked autophagic flux in cultured DCs. Furthermore, our results confirmed that TFEB or TFE3 knockdown exacerbated the disorders of lysosome and the blockade of autophagic flux in As-exposed DCs, and also enhanced the inhibitory expression of co-stimulatory molecules Cd80 and Cd83; adhesion molecule Icam1; cytokines TNF-α, IL-1β, and IL-6; chemokine receptor Ccr7; and antigen-presenting molecules MHC II and MHC I. By contrast, overexpression of TFEB or TFE3 partially alleviated the above-mentioned impairment of DCs by inorganic As exposure. In conclusion, these findings reveal a previously unappreciated inhibition of lysosome-mediated degradation and damage of lysosomal membrane integrity leading to dysregulated autophagy and impaired immune functions of DCs by arsenicals, and also suggest TFEB and TFE3 as potential therapeutic targets for ameliorating As toxicity.
    Keywords:  Autophagy; Dendritic cells; Inorganic arsenic; Lysosome; TFE3; TFEB
    DOI:  https://doi.org/10.1007/s10565-024-09841-0
  22. Antioxid Redox Signal. 2024 Jan 22.
    Beclin-1 haploinsufficiency ameliorates high fat diet-induced myocardial injury via inhibiting alternative mitophagy.
    Xiaofang Zeng, Jing Sun, Famei Li, Liming Peng, Chenglong Zhang, Xiaowei Jiang, Lihuang Zha, Anandharajan Rathinasabapathy, Jun Ren, Zaixin Yu, Lin Wang, Xiangwei Liu.
      AIM: Mitochondrial homeostasis is essential for maintaining redox balance. Besides canonical autophagy, Rab9-dependent alternative mitophagy is a crucial mechanism in metabolic cardiomyopathy. Here, we aim to investigate the role of alternative mitophagy and Beclin 1 haploinsufficiency (Beclin 1+/-) in high-fat diet (HFD)-induced metabolic cardiomyopathy.RESULTS: 24-week HFD impaired glucose tolerance and cardiomyocyte contraction in WT mice, both of which were rescued in Beclin 1+/- mice. Beclin 1 haploinsufficiency had little effect on the conventional autophagy mediators (ATG5, LC3II/LC3I) but further upregulated Rab9 expression, a marker of alternative autophagy, in response to HFD challenge. Furthermore, either the inhibition of alternative autophagy or Beclin 1 haploinsufficiency abolished palmitic acid-induced cardiomyocyte contractile anomalies. In vitro, palmitic acid over-activated mitophagy, resulting in decreased mitochondrial content in H9C2 cells. These aberrations were alleviated in cells deficient in alternative autophagy but not in cells deficient in conventional autophagy. Mechanistically, HFD promoted ROS production, activated Rab9-dependent alternative mitophagy, and inhibited mitochondrial biosynthesis. Beclin 1+/- rescued HFD-induced ROS overflow, mitochondrial biogenesis impairment, and prevented Rab9 translocation from the cytoplasm to the mitochondria, thereby inhibiting Rab9-mediated mitophagy over-activation.
    INNOVATION: For the first time, this study suggests that prolonged alternative mitophagy exacerbates chronic HFD-induced cardiac dysfunction and supports the protective role of Beclin 1 haploinsufficiency in metabolic cardiomyopathy. This provides additional evidence for a target-based pharmacological intervention.
    CONCLUSIONS: Beclin 1 haploinsufficiency protects against HFD-induced cardiac dysfunction by inhibiting Rab9-dependent alternative mitophagy and ROS production, while promoting mitochondrial biogenesis. Modulating Beclin 1 expression holds promise in preventing chronic HFD-related cardiomyopathy.
    DOI:  https://doi.org/10.1089/ars.2023.0399
  23. Molecules. 2024 Jan 18. pii: 482. [Epub ahead of print]29(2):
    Inhibition of VHL by VH298 Accelerates Pexophagy by Activation of HIF-1α in HeLa Cells.
    Yong Hwan Kim, Na Yeon Park, Doo Sin Jo, Ji-Eun Bae, Joon Bum Kim, Kyuhee Park, Kwiwan Jeong, Pansoo Kim, Eunbyul Yeom, Dong-Hyung Cho.
      Autophagy is a pivotal biological process responsible for maintaining the homeostasis of intracellular organelles. Yet the molecular intricacies of peroxisomal autophagy (pexophagy) remain largely elusive. From a ubiquitin-related chemical library for screening, we identified several inhibitors of the Von Hippel-Lindau (VHL) E3 ligase, including VH298, thereby serving as potent inducers of pexophagy. In this study, we observed that VH298 stimulates peroxisomal degradation by ATG5 dependently and escalates the ubiquitination of the peroxisomal membrane protein ABCD3. Interestingly, the ablation of NBR1 is similar to the curtailed peroxisomal degradation in VH298-treated cells. We also found that the pexophagy induced by VH298 is impeded upon the suppression of gene expression by the translation inhibitor cycloheximide. Beyond VHL inhibition, we discovered that roxadustat, a direct inhibitor of HIF-α prolyl hydroxylase, is also a potent inducer of pexophagy. Furthermore, we found that VH298-mediated pexophagy is blocked by silencing HIF-1α. In conclusion, our findings suggest that VH298 promotes pexophagy by modulating VHL-mediated HIF-α transcriptional activity.
    Keywords:  HIF-α; VH298; VHL E3 ligase; autophagy; pexophagy
    DOI:  https://doi.org/10.3390/molecules29020482
  24. Int J Mol Sci. 2024 Jan 19. pii: 1220. [Epub ahead of print]25(2):
    The Dual Role of Sulforaphane-Induced Cellular Stress-A Systems Biological Study.
    Marianna Holczer, Boglárka Besze, Annamária Lehel, Orsolya Kapuy.
      The endoplasmic reticulum (ER) plays a crucial role in cellular homeostasis. When ER stress is generated, an autophagic self-digestive process is activated to promote cell survival; however, cell death is induced in the case of excessive levels of ER stress. The aim of the present study was to investigate the effect of a natural compound called sulforaphane (SFN) upon ER stress. Our goal was to investigate how SFN-dependent autophagy activation affects different stages of ER stress induction. We approached our scientific analysis from a systems biological perspective using both theoretical and molecular biological techniques. We found that SFN induced the various cell-death mechanisms in a concentration- and time-dependent manner. The short SFN treatment at low concentrations promoted autophagy, whereas the longer treatment at higher concentrations activated cell death. We proved that SFN activated autophagy in a mTORC1-dependent manner and that the presence of ULK1 was required for its function. A low concentration of SFN pre- or co-treatment combined with short and long ER stress was able to promote cell survival via autophagy induction in each treatment, suggesting the potential medical importance of SFN in ER stress-related diseases.
    Keywords:  autophagy; cellular stress; feedback loops; sulforaphane; systems biology
    DOI:  https://doi.org/10.3390/ijms25021220
  25. Bot Stud. 2024 Jan 26. 65(1): 5
    Dynamic organelle changes and autophagic processes in lily pollen germination.
    Chih-Chung Yen, Chia-Mei Hsu, Pei-Luen Jiang, Guang-Yuh Jauh.
      Pollen germination is a crucial process in the life cycle of flowering plants, signifying the transition of quiescent pollen grains into active growth. This study delves into the dynamic changes within organelles and the pivotal role of autophagy during lily pollen germination. Initially, mature pollen grains harbor undifferentiated organelles, including amyloplasts, mitochondria, and the Golgi apparatus. However, germination unveils remarkable transformations, such as the redifferentiation of amyloplasts accompanied by starch granule accumulation. We investigate the self-sustained nature of amylogenesis during germination, shedding light on its association with osmotic pressure. Employing BODIPY 493/503 staining, we tracked lipid body distribution throughout pollen germination, both with or without autophagy inhibitors (3-MA, NEM). Typically, lipid bodies undergo polarized movement from pollen grains into elongating pollen tubes, a process crucial for directional growth. Inhibiting autophagy disrupted this essential lipid body redistribution, underscoring the interaction between autophagy and lipid body dynamics. Notably, the presence of tubular endoplasmic reticulum (ER)-like structures associated with developing amyloplasts and lipid bodies implies their participation in autophagy. Starch granules, lipid bodies, and membrane remnants observed within vacuoles further reinforce the involvement of autophagic processes. Among the autophagy inhibitors, particularly BFA, significantly impede germination and growth, thereby affecting Golgi morphology. Immunogold labeling substantiates the pivotal role of the ER in forming autophagosome-like compartments and protein localization. Our proposed speculative model of pollen germination encompasses proplastid differentiation and autophagosome formation. This study advances our understanding of organelle dynamics and autophagy during pollen germination, providing valuable insights into the realm of plant reproductive physiology.
    Keywords:  Autophagy; Organelle dynamics; Pollen germination; Vacuole formation
    DOI:  https://doi.org/10.1186/s40529-024-00410-6
  26. J Infect Dis. 2024 Jan 24. pii: jiae030. [Epub ahead of print]
    Heparin-binding hemagglutinin of Mycobacterium tuberculosis inhibits autophagy via TLR4 and drives M2 polarization in macrophages.
    Qing Zheng, Zhi Li, Yu Zhou, Yuru Li, Meiliang Gong, Heqiang Sun, Xinli Deng, Yueyun Ma.
      BACKGROUND: Tuberculosis (TB), predominantly caused by Mycobacterium tuberculosis (MTB) infection, remains a prominent global health challenge. Macrophages are the frontline defense against MTB, relying on autophagy for intracellular bacterial clearance. However, MTB can combat and evade autophagy, and it influences macrophage polarization, facilitating immune evasion and promoting infection. We previously found that heparin-binding hemagglutinin (HBHA) inhibits autophagy in A549 cells; however, its role in macrophage autophagy and polarization remains unclear.METHODS: Bacterial cultures, cell cultures, western blotting, immunofluorescence, macrophage infection assays, siRNA knockdown, and ELISA were used to investigate HBHA's impact on macrophages and its relevance in Mycobacterium infection.
    RESULTS: HBHA inhibited macrophage autophagy. Expression of recombinant HBHA in Mycobacterium smegmatis (rMS-HBHA) inhibited autophagy, promoting bacterial survival within macrophages. Conversely, HBHA knockout in the Mycobacterium bovis Bacillus Calmette-Guérin (BCG) mutant (BCG-ΔHBHA) activated autophagy and reduced bacterial survival. Mechanistic investigations revealed that HBHA may inhibit macrophage autophagy through the TLR4-dependent PI3K-AKT-mTOR signaling pathway. Furthermore, HBHA induced macrophage M2 polarization.
    CONCLUSIONS: Mycobacterium may exploit HBHA to suppress the antimicrobial immune response in macrophages, facilitating intracellular survival, and immune evasion through autophagy inhibition and M2 polarization induction. Our findings may help identify novel therapeutic targets and develop more effective treatments against MTB infection.
    Keywords:  HBHA; TLR4; autophagy; macrophage; polarization
    DOI:  https://doi.org/10.1093/infdis/jiae030
  27. Mitochondrion. 2024 Jan 19. pii: S1567-7249(24)00005-9. [Epub ahead of print]75 101847
    Mitochondrial dynamics and mitochondrial autophagy: Molecular structure, orchestrating mechanism and related disorders.
    Haoran Wang, Wenjun Luo, Haoyu Chen, Zhiduan Cai, Guibin Xu.
      Mitochondrial dynamics and autophagy play essential roles in normal cellular physiological activities, while abnormal mitochondrial dynamics and mitochondrial autophagy can cause cancer and related disorders. Abnormal mitochondrial dynamics usually occur in parallel with mitochondrial autophagy. Both have been reported to have a synergistic effect and can therefore complement or inhibit each other. Progress has been made in understanding the classical mitochondrial PINK1/Parkin pathway and mitochondrial dynamical abnormalities. Still, the mechanisms and regulatory pathways underlying the interaction between mitophagy and mitochondrial dynamics remain unexplored. Like other existing reviews, we review the molecular structure of proteins involved in mitochondrial dynamics and mitochondrial autophagy, and how their abnormalities can lead to the development of related diseases. We will also review the individual or synergistic effects of abnormal mitochondrial dynamics and mitophagy leading to cellular proliferation, differentiation and invasion. In addition, we explore the mechanisms underlying mitochondrial dynamics and mitochondrial autophagy to contribute to targeted and precise regulation of mitochondrial function. Through the study of abnormal mitochondrial dynamics and mitochondrial autophagy regulation mechanisms, as well as the role of early disease development, effective targets for mitochondrial function regulation can be proposed to enable accurate diagnosis and treatment of the associated disorders.
    Keywords:  Mitochondrial autophagy; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Orchestrating mechanism
    DOI:  https://doi.org/10.1016/j.mito.2024.101847
  28. Cell Death Discov. 2024 Jan 24. 10(1): 46
    Crosstalk between autophagy and metabolism: implications for cell survival in acute myeloid leukemia.
    Yongfeng Chen, Jia Chen, Zhenyou Zou, Linglong Xu, Jing Li.
      Acute myeloid leukemia (AML), a prevalent form of leukemia in adults, is often characterized by low response rates to chemotherapy, high recurrence rates, and unfavorable prognosis. A critical barrier in managing refractory or recurrent AML is the resistance to chemotherapy. Increasing evidence indicates that tumor cell metabolism plays a crucial role in AML progression, survival, metastasis, and treatment resistance. Autophagy, an essential regulator of cellular energy metabolism, is increasingly recognized for its role in the metabolic reprogramming of AML. Autophagy sustains leukemia cells during chemotherapy by not only providing energy but also facilitating rapid proliferation through the supply of essential components such as amino acids and nucleotides. Conversely, the metabolic state of AML cells can influence the activity of autophagy. Their mutual coordination helps maintain intrinsic cellular homeostasis, which is a significant contributor to chemotherapy resistance in leukemia cells. This review explores the recent advancements in understanding the interaction between autophagy and metabolism in AML cells, emphasizing their roles in cell survival and drug resistance. A comprehensive understanding of the interplay between autophagy and leukemia cell metabolism can shed light on leukemia cell survival strategies, particularly under adverse conditions such as chemotherapy. This insight may also pave the way for innovative targeted treatment strategies.
    DOI:  https://doi.org/10.1038/s41420-024-01823-9
  29. Front Pharmacol. 2023 ;14 1266311
    Role of ATG7-dependent non-autophagic pathway in angiogenesis.
    Jinxiang Chen, Yu Liang, Shaorun Hu, Jun Jiang, Min Zeng, Mao Luo.
      ATG7, one of the core proteins of autophagy, plays an important role in various biological processes, including the regulation of autophagy. While clear that autophagy drives angiogenesis, the role of ATG7 in angiogenesis remains less defined. Several studies have linked ATG7 with angiogenesis, which has long been underappreciated. The knockdown of ATG7 gene in cerebrovascular development leads to angiogenesis defects. In addition, specific knockout of ATG7 in endothelial cells results in abnormal development of neovascularization. Notably, the autophagy pathway is not necessary for ATG7 regulation of angiogenesis, while the ATG7-dependent non-autophagic pathway plays a critical role in the regulation of neovascularization. In order to gain a better understanding of the non-autophagic pathway-mediated biological functions of the autophagy-associated protein ATG7 and to bring attention to this expanding but understudied research area, this article reviews recent developments in the ATG7-dependent non-autophagic pathways regulating angiogenesis.
    Keywords:  ATG7; NF-κB; STAT1; angiogenesis; non-autophagic pathway
    DOI:  https://doi.org/10.3389/fphar.2023.1266311
  30. Traffic. 2024 Jan;25(1): e12925
    Mechanisms regulating the intracellular trafficking and release of CLN5 and CTSD.
    Robert J Huber, William D Kim, Morgan L D M Wilson-Smillie.
      Ceroid lipofuscinosis neuronal 5 (CLN5) and cathepsin D (CTSD) are soluble lysosomal enzymes that also localize extracellularly. In humans, homozygous mutations in CLN5 and CTSD cause CLN5 disease and CLN10 disease, respectively, which are two subtypes of neuronal ceroid lipofuscinosis (commonly known as Batten disease). The mechanisms regulating the intracellular trafficking of CLN5 and CTSD and their release from cells are not well understood. Here, we used the social amoeba Dictyostelium discoideum as a model system to examine the pathways and cellular components that regulate the intracellular trafficking and release of the D. discoideum homologs of human CLN5 (Cln5) and CTSD (CtsD). We show that both Cln5 and CtsD contain signal peptides for secretion that facilitate their release from cells. Like Cln5, extracellular CtsD is glycosylated. In addition, Cln5 release is regulated by the amount of extracellular CtsD. Autophagy induction promotes the release of Cln5, and to a lesser extent CtsD. Release of Cln5 requires the autophagy proteins Atg1, Atg5, and Atg9, as well as autophagosomal-lysosomal fusion. Atg1 and Atg5 are required for the release of CtsD. Together, these data support a model where Cln5 and CtsD are actively released from cells via their signal peptides for secretion and pathways linked to autophagy. The release of Cln5 and CtsD from cells also requires microfilaments and the D. discoideum homologs of human AP-3 complex mu subunit, the lysosomal-trafficking regulator LYST, mucopilin-1, and the Wiskott-Aldrich syndrome-associated protein WASH, which all regulate lysosomal exocytosis in this model organism. These findings suggest that lysosomal exocytosis also facilitates the release of Cln5 and CtsD from cells. In addition, we report the roles of ABC transporters, microtubules, osmotic stress, and the putative D. discoideum homologs of human sortilin and cation-independent mannose-6-phosphate receptor in regulating the intracellular/extracellular distribution of Cln5 and CtsD. In total, this study identifies the cellular mechanisms regulating the release of Cln5 and CtsD from D. discoideum cells and provides insight into how altered trafficking of CLN5 and CTSD causes disease in humans.
    Keywords:  ABC transporters; Batten disease; autophagy; cytoskeleton; exocytosis; glycosylation; lysosome; neuronal ceroid lipofuscinosis; osmoregulation
    DOI:  https://doi.org/10.1111/tra.12925
  31. ACS Nano. 2024 Jan 26.
    Biomimetic Nanomedicine Targeting Orchestrated Metabolism Coupled with Regulatory Factors to Disrupt the Metabolic Plasticity of Breast Cancer.
    Lingtong Meng, Jingpeng Yang, Yang Gao, Qinyan Cao, Shunjie Jiang, Yuyang Xiao, Haoran Wang, Wenzheng Liu, Ahu Yuan, Yanan Li, He Huang.
      Targeting nutrient metabolism has been proposed as an effective therapeutic strategy to combat breast cancer because of its high nutrient requirements. However, metabolic plasticity enables breast cancer cells to survive under unfavorable starvation conditions. The key mammalian target regulators rapamycin (mTOR) and hypoxia-inducible-factor-1 (HIF-1) tightly link the dynamic metabolism of glutamine and glucose to maintain nutrient flux. Blocking nutrient flow also induces autophagy to recycle nutrients in the autophagosome, which exacerbates metastasis and tumor progression. Compared to other common cancers, breast cancer is even more dependent on mTOR and HIF-1 to orchestrate the metabolic network. Therefore, we develop a cascade-boosting integrated nanomedicine to reprogram complementary metabolism coupled with regulators in breast cancer. Glucose oxidase efficiently consumes glucose, while the delivery of rapamycin inside limits the metabolic flux of glutamine and uncouples the feedback regulation of mTOR and HIF-1. The hydroxyl radical generated in a cascade blocks the later phase of autophagy without nutrient recycling. This nanomedicine targeting orchestrated metabolism can disrupt the coordination of glucose, amino acids, nucleotides, lipids, and other metabolic pathways in breast cancer tissues, effectively improving the durable antitumor effect and prognosis of breast cancer. Overall, the cascade-boosting integrated system provides a viable strategy to address cellular plasticity and efficient enzyme delivery.
    Keywords:  autophagy; glucose metabolism; glutamine metabolism; metabolic plasticity; nanomedicine
    DOI:  https://doi.org/10.1021/acsnano.3c10129
  32. Front Pharmacol. 2023 ;14 1332567
    The potential influence of melatonin on mitochondrial quality control: a review.
    Xudan Lei, Zhenni Xu, Lingxiao Huang, Yujun Huang, Siyu Tu, Lu Xu, Dengqun Liu.
      Mitochondria are critical for cellular energetic metabolism, intracellular signaling orchestration and programmed death regulation. Therefore, mitochondrial dysfunction is associated with various pathogeneses. The maintenance of mitochondrial homeostasis and functional recovery after injury are coordinated by mitochondrial biogenesis, dynamics and autophagy, which are collectively referred to as mitochondrial quality control. There is increasing evidence that mitochondria are important targets for melatonin to exert protective effects under pathological conditions. Melatonin, an evolutionarily conserved tryptophan metabolite, can be synthesized, transported and metabolized in mitochondria. In this review, we summarize the important role of melatonin in the damaged mitochondria elimination and mitochondrial energy supply recovery by regulating mitochondrial quality control, which may provide new strategies for clinical treatment of mitochondria-related diseases.
    Keywords:  autophagy; melatonin; mitochondria-related diseases; mitochondrial dynamics; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fphar.2023.1332567
  33. Biochem Biophys Res Commun. 2024 Jan 23. pii: S0006-291X(24)00099-8. [Epub ahead of print]699 149564
    Psychological stress induces hair regenerative disorders through corticotropin-releasing hormone-mediated autophagy inhibition.
    Wenzi Liang, Yinglin Zhao, Bozhi Cai, Yuxin Huang, Xiuwen Chen, Na Ni, Yingshan Wang, Zhaoping Lin, Changmin Lin, Keng Huang.
      Psychosocial stress is increasing, causing a growing number of people to suffer from hair loss. Stress-related corticotropin-releasing hormone (CRH) is associated with hair loss, but the mechanism by which hair follicles respond to stress and CRH remain poorly understood. The aim of the study is to elucidate the association between CRH and stress-related hair regenerative disorders, and reveal the potential pathological mechanisms. A chronic unpredictable stress mouse model and a chronic social defeat stress mouse model were used to examine the role of CRH and stress-related hair regrowth. Chronic unpredictable stress and chronic social defeat stress increased the expression of CRH and CRH receptors (CRHRs), and contributed to the onset of hair-cycle abnormalities. Psychoemotional stress and stress-related CRH blocked hair follicle regrowth, which could be restored by astressin, a CRHR antagonist. Long-term exposure to either chronic unpredictable stress or CRH induced a decrease in autophagy, which could be partially rescued by astressin. Activating CRHR, by stress or CRH administration, decreased autophagy via the mTOR-ULK1 signaling pathway to mediate hair regenerative disorders, which could be partially reversed through enhancing autophagy by administration of brefeldin A. These findings indicate that CRH-mediated autophagy inhibition play an important role in stress-induced hair regenerative disorders. CRH regulates the local hypothalamic-pituitary-adrenal axis of hair follicles, but also plays an independent pathogenic role in stress-related hair regenerative disorders through CRH-mediated autophagy inhibition. This work contributes to the present understanding of hair loss and suggests that enhancing autophagy may have a therapeutic effect on stress-induced hair loss.
    Keywords:  Autophagy; Chronic unpredictable stress; Corticotropin-releasing hormone; Corticotropin-releasing hormone receptors; Hair loss
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149564
  34. J Biol Chem. 2024 Jan 19. pii: S0021-9258(24)00038-3. [Epub ahead of print] 105662
    Methionine sulfoxide reductase 2 regulates Cvt autophagic pathway by altering the stability of Atg19 and Ape1 in Saccharomyces cerevisiae.
    Arpan Chatterjee, Naresh Babu V Sepuri.
      The reversible oxidation of methionine plays a crucial role in redox regulation of proteins. Methionine oxidation in proteins causes major structural modifications that can destabilize and abrogate their function. The highly conserved methionine sulfoxide reductases (MSRs) protect proteins from oxidative damage by reducing their oxidized methionines, thus restoring their stability and function. Deletion or mutation in conserved MSRs leads to aging and several human neurological disorders and also reduces yeast growth on non-fermentable carbon sources. Despite their importance in human health, limited information about their physiological substrates in humans and yeast is available. For the first time, we show that Mxr2 interacts in vivo with two core proteins of the Cvt autophagy pathway, Atg19, and Ape1 in Saccharomyces cerevisiae. Deletion of MXR2 induces instability and early turnover of immature Ape1 and Atg19 proteins and reduces the leucine aminopeptidase activity of Ape1 without affecting the maturation process of Ape1. Additonally, Mxr2 interacts with the immature Ape1, dependent on Met17 present within the propeptide of Ape1 as a single substitution mutation of Met17 to Leu abolishes this interaction. Importantly, Ape1 M17L mutant protein resists oxidative stress-induced degradation in wild-type and mxr2Δ cells. By identifying Atg19 and Ape1 as cytosolic substrates of Mxr2, our study maps the hitherto unexplored connection between Mxr2 and the Cvt autophagy pathway and sheds light on Mxr2-dependent oxidative regulation of the Cvt pathway.
    Keywords:  Ape1; Atg19; Cvt pathway; Methionine oxidation; Methionine sulfoxide reductase 2 (Mxr2); Reactive Oxygen Species; Redox regulation
    DOI:  https://doi.org/10.1016/j.jbc.2024.105662
  35. Virol Sin. 2024 Jan 23. pii: S1995-820X(24)00005-1. [Epub ahead of print]
    PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity.
    Ruiqi Sun, Yanyu Guo, Lilin Zhang, Huixia Zhang, Boxuan Yin, Xiaoyang Li, Changyan L, Liu Yang, Lei Zhang, Zexing Li, Jinhai Huang.
      Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically devastating pathogen that has evolved various strategies to evade innate immunity. Downregulation of antiviral interferon largely contributes to PRRSV immunoevasion through cytoplasmic melanoma differentiation-associated gene 5 (MDA5), a receptor that senses viral RNA. In this study, the downregulated transcription and expression levels of porcine MDA5 in PRRSV infection were observed, but the detailed mechanisms remain unclear. The interaction between P62 and MDA5 was strengthened due to the phosphorylation modification of the autophagic receptor P62 by the upregulated kinase CK2α and the K63 ubiquitination of porcine MDA5 catalyzed by the E3 ubiquitinase TRIM21 in PRRSV-infected cells, thus triggering the classic P62-mediated autophagy. Additionally, porcine MDA5 interacted with the chaperonin containing TCP1 subunit 2 (CCT2) and was enhanced by PRRSV nsp3, facilitating the aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 independently of ubiquitin. Enhanced MDA5 degradation occurs in PRRSV infection via two autophagic pathways, including the binding of MDA5 with the autophagy receptor P62 and the aggrephagy receptor CCT2, triggering intense innate immune suppression. The research reveals a novel mechanism of immune evasion in PRRSV infection and provides fundamental insights for the development of new vaccines or therapeutic strategies.
    Keywords:  MDA5; Porcine reproductive and respiratory syndrome virus (PRRSV); autophagy; nsp3
    DOI:  https://doi.org/10.1016/j.virs.2024.01.005
  36. FASEB J. 2024 Jan 31. 38(2): e23429
    Treatment with sodium butyrate induces autophagy resulting in therapeutic benefits for spinocerebellar ataxia type 3.
    Maxinne Watchon, Katherine J Robinson, Luan Luu, Yousun An, Kristy C Yuan, Stuart K Plenderleith, Flora Cheng, Emily K Don, Garth A Nicholson, Albert Lee, Angela S Laird.
      Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of ataxin-3 protein aggregates, neurodegeneration, and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH-SY5Y cells and transgenic zebrafish expressing human ataxin-3 containing 84 glutamine (Q) residues to model SCA3. SCA3 SH-SY5Y cells were found to contain high molecular weight ataxin-3 species and detergent-insoluble protein aggregates. Treatment with SB increased the activity of the autophagy protein quality control pathway in the SCA3 cells, decreased the presence of ataxin-3 aggregates and presence of high molecular weight ataxin-3 in an autophagy-dependent manner. Treatment with SB was also beneficial in vivo, improving swimming performance, increasing activity of the autophagy pathway, and decreasing the presence of insoluble ataxin-3 protein species in the transgenic SCA3 zebrafish. Co-treating the SCA3 zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on zebrafish swimming, indicating that the improved swimming performance was autophagy-dependent. To understand the mechanism by which SB induces autophagy we performed proteomic analysis of protein lysates from the SB-treated and untreated SCA3 SH-SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signaling, with immunoblot analysis confirming that SB treatment had increased levels of AMPK protein and its substrates. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway process and that this has beneficial effects in vitro and in vivo. While our results suggested that this activity may involve activity of a PKA/AMPK-dependent process, this requires further confirmation. We propose that treatment with sodium butyrate warrants further investigation as a potential treatment for neurodegenerative diseases underpinned by mechanisms relating to protein aggregation including SCA3.
    Keywords:  Machado-Joseph disease; autophagy; neurodegeneration; polyQ; sodium butyrate; spinocerebellar ataxia type 3; trinucleotide repeat disease; zebrafish
    DOI:  https://doi.org/10.1096/fj.202300963RR
  37. Development. 2024 Jan 24. pii: dev.202231. [Epub ahead of print]
    Fluctuation of lysosomal protein degradation in neural stem cells of the postnatal mouse brain.
    He Zhang, Karan Ishii, Tatsuya Shibata, Shunsuke Ishii, Marika Hirao, Zhou Lu, Risa Takamura, Satsuki Kitano, Hitoshi Miyachi, Ryoichiro Kageyama, Eisuke Itakura, Taeko Kobayashi.
      Lysosomes are intracellular organelles responsible for degrading diverse macromolecules delivered from several pathways, including the endo-lysosomal and autophagic pathways. Recent reports have suggested that lysosomes are essential for regulating neural stem cells in developing, adult, and aged brains. However, the activity of these lysosomes has yet to be monitored in these brain tissues. Here, we report the development of a new probe to measure lysosomal protein degradation in brain tissue by immunostaining. Our results indicate that lysosomal protein degradation fluctuates in neural stem cells of the hippocampal dentate gyrus, depending on age and brain disorders. Neural stem cells increase their lysosomal activity during hippocampal development in the dentate gyrus, but aging and aging-related disease reduce lysosomal activity. In addition, physical exercise increases lysosomal activity in neural stem cells and astrocytes in the dentate gyrus. We therefore propose that three different stages of lysosomal activity exist: the state of increase during development, the stable state during adulthood, and the state of reduction due to damage caused by either age or disease.
    Keywords:  Adult brain; Dentate gyrus; Lysosomes; Neural stem cells; Protein degradation
    DOI:  https://doi.org/10.1242/dev.202231
  38. Int J Surg Pathol. 2024 Jan 22. 10668969231219653
    Mechanistic Target of Rapamycin Kinase is a Common Convergent Pathway to Renal Neoplasia: A Contemporary Review.
    Zainab I Alruwaii, Sean R Williamson, Khaleel I Al-Obaidy.
      Mechanistic target of rapamycin kinase (mTOR) is a member of the phosphatidylinositol-3-hydroxide kinase (PI3 K)-related protein kinase family that functions as a central regulator of cell growth, metabolism, proliferation, and survival. The role of the TSC-mTOR signaling pathway in kidney tumors has been implicated in some hamartoma syndromes; however, with the advent and wide utilization of molecular studies, a growing number of kidney tumors have been linked to somatic or germline mutations involving genes that encode for this pathway, including eosinophilic solid and cystic renal cell carcinoma, low-grade oncocytic tumor, eosinophilic vacuolated tumor, renal cell carcinoma with fibromyomatous stroma and angiomyolipoma, among others. Herein, we review the contemporary developments of mTOR pathway-related renal neoplasia, focusing on the clinicopathologic features of the tumor entities.
    Keywords:  kidney, tuberous sclerosis, MTOR, renal cell, tumor, carcinoma
    DOI:  https://doi.org/10.1177/10668969231219653
  39. Biochem Biophys Res Commun. 2024 Jan 19. pii: S0006-291X(24)00086-X. [Epub ahead of print]699 149551
    A pH imbalance is linked to autophagic dysregulation of inner ear hair cells in Atp6v1ba-deficient zebrafish.
    Mayo Ikeuchi, Masanori Inoue, Hiroaki Miyahara, Wulan Apridita Sebastian, Shuya Miyazaki, Takashi Takeno, Kyoko Kiyota, Shinji Yano, Hiroshi Shiraishi, Nobuyuki Shimizu, Reiko Hanada, Akihiko Yoshimura, Kenji Ihara, Toshikatsu Hanada.
      V-ATPase is an ATP hydrolysis-driven proton pump involved in the acidification of intracellular organelles and systemic acid-base homeostasis through H+ secretion in the renal collecting ducts. V-ATPase dysfunction is associated with hereditary distal renal tubular acidosis (dRTA). ATP6V1B1 encodes the B1 subunit of V-ATPase that is integral to ATP hydrolysis and subsequent H+ transport. Patients with pathogenic ATP6V1B1 mutations often exhibit an early onset of sensorineural hearing loss. However, the mechanisms underlying this association remain unclear. We employed morpholino oligonucleotide-mediated knockdown and CRISPR/Cas9 gene editing to generate Atp6v1ba-deficient (atp6v1ba-/-) zebrafish as an ortholog model for ATP6V1B1. The atp6v1ba-/- zebrafish exhibited systemic acidosis and significantly smaller otoliths compared to wild-type siblings. Moreover, deficiency in Atp6v1ba led to degeneration of inner ear hair cells, with ultrastructural changes indicative of autophagy. Our findings indicate a critical role of ATP6V1B1 in regulating lysosomal pH and autophagy in hair cells, and the results provide insights into the pathophysiology of sensorineural hearing loss in dRTA. Furthermore, this study demonstrates that the atp6v1ba-/- zebrafish model is a valuable tool for further investigation into disease mechanisms and potential therapies for acidosis-related hearing impairment.
    Keywords:  ATP6V1B1; Atp6v1ba; Hearing loss; V-ATPase; Zebrafish; dRTA
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149551
  40. Toxicol Appl Pharmacol. 2024 Jan 23. pii: S0041-008X(24)00034-6. [Epub ahead of print] 116836
    The skin photoprotective effect of trilinolein: Induction of cellular autophagy via the AMPK-mTOR signaling pathway.
    Xianghong Lin, Na Deng, Huijuan Li, Jingxian Duan, Wenqiu Chen, Tao Liu, Sujiao Sun, Jimin Chu.
      Trilinolein (TL) is an active substance contained in traditional Chinese herbs; modern studies have shown that trilinolein has anti-inflammatory and antioxidant effects on the body. This study delves into the photoprotective effect of trilinolein on UVB-irradiated Human Skin Fibroblast (HSF) cells and the underlying mechanisms. Our findings reveal that trilinolein had a photoprotective effect on HSF cells: trilinolein enhanced cellular autophagy, restored UVB-inhibited cell proliferative viability, and curbing UVB-induced reactive oxygen species (ROS) and apoptosis. Intriguingly, after inhibition of TL-induced autophagy via wortmannin, diminished trilinolein's photoprotective effects. Meanwhile, trilinolein was shown to modulate the AMPK-mTOR signaling pathway, thus enhance cellular autophagy in HSF cells, and this tendency was suppressed after the administration of compound C (AMPK inhibitor). In a mouse model of skin photodamage, trilinolein significantly mitigated photodamage extent through morphological and histopathological analyses. This study illuminates trilinolein could inhibit the photodamaging effects of UVB irradiation by regulating cellular autophagy through the AMPK-mTOR signaling pathway, suggesting its promising application in combating UV-induced skin disorders.
    Keywords:  Autophagy; HSF; Photodamage; Skin; Trilinolein; UVB
    DOI:  https://doi.org/10.1016/j.taap.2024.116836
  41. Biomedicines. 2023 Dec 19. pii: 5. [Epub ahead of print]12(1):
    Interaction of Tau with Kinesin-1: Effect of Kinesin-1 Heavy Chain Elimination on Autophagy-Mediated Mutant Tau Degradation.
    Karthikeyan Selvarasu, Abhay Kumar Singh, Avinash Dakshinamoorthy, Sravan Gopalkrishnashetty Sreenivasmurthy, Ashok Iyaswamy, Moorthi Radhakrishnan, Supriti Patnaik, Jian-Dong Huang, Leonard L Williams, Sanjib Senapati, Siva Sundara Kumar Durairajan.
      Natively unfolded tau has a low propensity to form aggregates, but in tauopathies, such as Alzheimer's disease (AD), tau aggregates into paired helical filaments (PHFs) and neurofibrillary tangles (NFTs). Multiple intracellular transport pathways utilize kinesin-1, a plus-end-directed microtubule-based motor. Kinesin-1 is crucial in various neurodegenerative diseases as it transports multiple cargoes along the microtubules (MT). Kinesin-1 proteins cannot progress along MTs due to an accumulation of tau on their surfaces. Although kinesin-1-mediated neuronal transport dysfunction is well-documented in other neurodegenerative diseases, its role in AD has received less attention. Very recently, we have shown that knocking down and knocking out of kinesin-1 heavy chain (KIF5B KO) expression significantly reduced the level and stability of tau in cells and tau transgenic mice, respectively. Here, we report that tau interacts with the motor domain of KIF5B in vivo and in vitro, possibly through its microtubule-binding repeat domain. This interaction leads to the inhibition of the ATPase activity of the motor domain. In addition, the KIF5B KO results in autophagy initiation, which subsequently assists in tau degradation. The mechanisms behind KIF5B KO-mediated tau degradation seem to involve its interaction with tau, promoting the trafficking of tau through retrograde transport into autophagosomes for subsequent lysosomal degradation of tau. Our results suggest how KIF5B removal facilitates the movement of autophagosomes toward lysosomes for efficient tau degradation. This mechanism can be enabled through the downregulation of kinesin-1 or the disruption of the association between kinesin-1 and tau, particularly in cases when neurons perceive disturbances in intercellular axonal transport.
    Keywords:  ATPase; Alzheimer’s disease; KIF5B; autophagy; kinesin 1 heavy chain; tau
    DOI:  https://doi.org/10.3390/biomedicines12010005
  42. Commun Biol. 2024 Jan 24. 7(1): 121
    Mobilization of cholesterol induces the transition from quiescence to growth in Caenorhabditis elegans through steroid hormone and mTOR signaling.
    Kathrin Schmeisser, Damla Kaptan, Bharath Kumar Raghuraman, Andrej Shevchenko, Jonathan Rodenfels, Sider Penkov, Teymuras V Kurzchalia.
      Recovery from the quiescent developmental stage called dauer is an essential process in C. elegans and provides an excellent model to understand how metabolic transitions contribute to developmental plasticity. Here we show that cholesterol bound to the small secreted proteins SCL-12 or SCL-13 is sequestered in the gut lumen during the dauer state. Upon recovery from dauer, bound cholesterol undergoes endocytosis into lysosomes of intestinal cells, where SCL-12 and SCL-13 are degraded and cholesterol is released. Free cholesterol activates mTORC1 and is used for the production of dafachronic acids. This leads to promotion of protein synthesis and growth, and a metabolic switch at the transcriptional level. Thus, mobilization of sequestered cholesterol stores is the key event for transition from quiescence to growth, and cholesterol is the major signaling molecule in this process.
    DOI:  https://doi.org/10.1038/s42003-024-05804-7
  43. Mol Med Rep. 2024 Mar;pii: 49. [Epub ahead of print]29(3):
    Larixyl acetate, a TRPC6 inhibitor, attenuates pressure overload‑induced heart failure in mice.
    Min Jia, Wenxue Liu, Keyin Zhang, Zhigang Wang, Ruisha Li, Jun Pan, Jianjun Yang, Dongjin Wang.
      Heart failure is a primary cause of global mortality. In the present study, whether larixyl acetate, an inhibitor of transient receptor potential cation channel subfamily C member 6, attenuates pressure overload‑induced heart failure in mice was investigated. To test this hypothesis, a transverse aortic constriction (TAC) animal model and an angiotensin II (Ang II)‑treated H9c2 cell model were used. Cardiac and cellular structure, function and the expression levels of hypertrophy, endoplasmic reticulum (ER) stress, apoptosis, autophagy and pmTOR/mTOR related mRNAs or proteins were assessed to explore the underlying molecular mechanisms. The results indicated that treatment with TAC or Ang II leads to significant hypertrophy and dysfunction of the heart or H9c2 cells, accompanied by an increase in ER stress, apoptosis and activation of the mTOR signaling pathway, and a decrease in autophagy. The administration of larixyl acetate attenuated these impairments, which can be reversed by inhibiting autophagy through the activation of the mTOR signaling pathway. These findings suggested that larixyl acetate can effectively protect against pressure overload‑induced heart failure by enhancing autophagy and limiting ER stress and apoptosis through inhibition of the mTOR pathway.
    Keywords:  apoptosis; autophagy; endoplasmic retitculum stress; larixyl acetate; mTOR
    DOI:  https://doi.org/10.3892/mmr.2024.13174
  44. Cells. 2024 Jan 17. pii: 178. [Epub ahead of print]13(2):
    ALS' Perfect Storm: C9orf72-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis.
    Paulien H Smeele, Giuliana Cesare, Thomas Vaccari.
      Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin-proteasome systems, maintains protein homeostasis in neurons, which are post-mitotic and thus cannot use cell division to diminish the burden of misfolded proteins. When protein clearance pathways are overwhelmed or otherwise disrupted, the accumulation of misfolded or aggregated proteins can lead to the activation of ER stress and the formation of stress granules, which predominantly attempt to restore the homeostasis by suppressing global protein translation. Alterations in these processes have been widely reported among studies investigating the toxic function of dipeptide repeats (DPRs) produced by G4C2 expansion in the C9orf72 gene of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review, we outline the modalities of DPR-induced disruptions in protein homeostasis observed in a wide range of models of C9orf72-linked ALS/FTD. We also discuss the relative importance of each DPR for toxicity, possible synergies between DPRs, and discuss the possible functional relevance of DPR aggregation to disease pathogenesis. Finally, we highlight the interdependencies of the observed effects and reflect on the importance of feedback and feedforward mechanisms in their contribution to disease progression. A better understanding of DPR-associated disease pathogenesis discussed in this review might shed light on disease vulnerabilities that may be amenable with therapeutic interventions.
    Keywords:  ALS; C9orf72; ER stress; FTD; autophagy; dipeptide repeats; lysosome; proteasome; protein homeostasis
    DOI:  https://doi.org/10.3390/cells13020178
  45. EMBO J. 2024 Jan 24.
    Shared structural features of Miro binding control mitochondrial homeostasis.
    Christian Covill-Cooke, Brian Kwizera, Guillermo López-Doménech, Caleb Od Thompson, Ngaam J Cheung, Ema Cerezo, Martin Peterka, Josef T Kittler, Benoît Kornmann.
      Miro proteins are universally conserved mitochondrial calcium-binding GTPases that regulate a multitude of mitochondrial processes, including transport, clearance, and lipid trafficking. The exact role of Miro in these functions is unclear but involves binding to a variety of client proteins. How this binding is operated at the molecular level and whether and how it is important for mitochondrial health, however, remains unknown. Here, we show that known Miro interactors-namely, CENPF, Trak, and MYO19-all use a similar short motif to bind the same structural element: a highly conserved hydrophobic pocket in the first calcium-binding domain of Miro. Using these Miro-binding motifs, we identified direct interactors de novo, including MTFR1/2/1L, the lipid transporters Mdm34 and VPS13D, and the ubiquitin E3-ligase Parkin. Given the shared binding mechanism of these functionally diverse clients and its conservation across eukaryotes, we propose that Miro is a universal mitochondrial adaptor coordinating mitochondrial health.
    Keywords:  AlphaFold; ERMES; Lipid Transport; Mitophagy; Organelle Transport
    DOI:  https://doi.org/10.1038/s44318-024-00028-1
  46. Int J Mol Sci. 2024 Jan 17. pii: 1123. [Epub ahead of print]25(2):
    Contribution of Autophagy to Cellular Iron Homeostasis and Stress Adaptation in Alternaria alternata.
    Pei-Ching Wu, Yen-Ling Choo, Sian-Yong Wei, Jonar I Yago, Kuang-Ren Chung.
      The tangerine pathotype of Alternaria alternata produces the Alternaria citri toxin (ACT), which elicits a host immune response characterized by the increase in harmful reactive oxygen species (ROS) production. ROS detoxification in A. alternata relies on the degradation of peroxisomes through autophagy and iron acquisition using siderophores. In this study, we investigated the role of autophagy in regulating siderophore and iron homeostasis in A. alternata. Our results showed that autophagy positively influences siderophore production and iron uptake. The A. alternata strains deficient in autophagy-related genes 1 and 8 (ΔAaatg1 and ΔAaatg8) could not thrive without iron, and their adaptability to high-iron environments was also reduced. Furthermore, the ability of autophagy-deficient strains to withstand ROS was compromised. Notably, autophagy deficiency significantly reduced the production of dimerumic acid (DMA), a siderophore in A. alternata, which may contribute to ROS detoxification. Compared to the wild-type strain, ΔAaatg8 was defective in cellular iron balances. We also observed iron-induced autophagy and lipid peroxidation in A. alternata. To summarize, our study indicates that autophagy and maintaining iron homeostasis are interconnected and contribute to the stress resistance and the virulence of A. alternata. These results provide new insights into the complex interplay connecting autophagy, iron metabolism, and fungal pathogenesis in A. alternata.
    Keywords:  ROS; filamentous fungi; labile iron pool; lipid peroxidation; pathogenicity; siderophore
    DOI:  https://doi.org/10.3390/ijms25021123
  47. Front Neurosci. 2023 ;17 1304080
    A pathogenic variant in the FLCN gene presenting with pure dementia: is autophagy at the intersection between neurodegeneration and cancer?
    Irene Bottillo, Luigi Laino, Alessia Azzarà, Carla Lintas, Ilaria Cassano, Vincenzo Di Lazzaro, Francesca Ursini, Francesco Motolese, Simone Bargiacchi, Daniela Formicola, Paola Grammatico, Fiorella Gurrieri.
      Introduction: Folliculin, encoded by FLCN gene, plays a role in the mTORC1 autophagy cascade and its alterations are responsible for the Birt-Hogg-Dubé (BHD) syndrome, characterized by follicle hamartomas, kidney tumors and pneumothorax.Patient and results: We report a 74-years-old woman diagnosed with dementia and carrying a FLCN alteration in absence of any sign of BHD. She also carried an alteration of MAT1A gene, which is also implicated in the regulation of mTORC1.
    Discussion: The MAT1A variant could have prevented the development of a FLCN-related oncological phenotype. Conversely, our patient presented with dementia that, to date, has yet to be documented in BHD. Folliculin belongs to the DENN family proteins, which includes C9orf72 whose alteration has been associated to neurodegeneration. The folliculin perturbation could affect the C9orf72 activity and our patient could represent the first human model of a relationship between FLCN and C9orf72 across the path of autophagy.
    Keywords:  Birt–Hogg–Dubé (BHD); FLCN; autophagy; dementia; folliculin; methionine
    DOI:  https://doi.org/10.3389/fnins.2023.1304080
  48. Cell Death Discov. 2024 Jan 26. 10(1): 50
    Glial senescence enhances α-synuclein pathology owing to its insufficient clearance caused by autophagy dysfunction.
    Bin Hong, Yosuke Ohtake, Takahide Itokazu, Toshihide Yamashita.
      Parkinson's disease (PD) is characterized by the pathological accumulation of α-synuclein (α-syn) and loss of dopaminergic neurons in the substantia nigra. Aging is a significant risk factor for PD. The accumulation of senescent glial cells in the aged brain contributes to PD progression by inducing chronic neuroinflammatory processes. However, although the insufficient degradation of α-syn aggregates results in PD deterioration, the possible alteration in the ability of α-syn clearance in senescent glia has received little attention. In this study, we investigated how aging and glial senescence affect the capacity of α-syn clearance. We found that following the intra-striatal injection of human α-syn (hu-α-syn) preformed fibril, hu-α-syn pathology persisted more in aged mice compared with younger mice and that aged microglia exhibited greater accumulation of hu-α-syn than younger microglia. Moreover, in vitro assay revealed that the clearance of hu-α-syn was primarily dependent on the autophagy-lysosome system rather than on the ubiquitin-proteasome system and that the capacity of hu-α-syn clearance was diminished in senescent glia because of autophagy-lysosome system dysfunction. Overall, this study provides new insights into the role of senescent glia in PD pathogenesis.
    DOI:  https://doi.org/10.1038/s41420-024-01816-8
  49. Int J Mol Sci. 2024 Jan 17. pii: 1125. [Epub ahead of print]25(2):
    Autophagy Markers Are Altered in Alzheimer's Disease, Dementia with Lewy Bodies and Frontotemporal Dementia.
    Antonio Longobardi, Marcella Catania, Andrea Geviti, Erika Salvi, Elena Rita Vecchi, Sonia Bellini, Claudia Saraceno, Roland Nicsanu, Rosanna Squitti, Giuliano Binetti, Giuseppe Di Fede, Roberta Ghidoni.
      The accumulation of protein aggregates defines distinct, yet overlapping pathologies such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). In this study, we investigated ATG5, UBQLN2, ULK1, and LC3 concentrations in 66 brain specimens and 120 plasma samples from AD, DLB, FTD, and control subjects (CTRL). Protein concentration was measured with ELISA kits in temporal, frontal, and occipital cortex specimens of 32 AD, 10 DLB, 10 FTD, and 14 CTRL, and in plasma samples of 30 AD, 30 DLB, 30 FTD, and 30 CTRL. We found alterations in ATG5, UBQLN2, ULK1, and LC3 levels in patients; ATG5 and UBQLN2 levels were decreased in both brain specimens and plasma samples of patients compared to those of the CTRL, while LC3 levels were increased in the frontal cortex of DLB and FTD patients. In this study, we demonstrate alterations in different steps related to ATG5, UBQLN2, and LC3 autophagy pathways in DLB and FTD patients. Molecular alterations in the autophagic processes could play a role in a shared pathway involved in the pathogenesis of neurodegeneration, supporting the hypothesis of a common molecular mechanism underlying major neurodegenerative dementias and suggesting different potential therapeutic targets in the autophagy pathway for these disorders.
    Keywords:  ATG5; Alzheimer’s disease; LC3; UBQLN2; ULK1; autophagy; brain; dementia with Lewy bodies; frontotemporal dementia; neurodegeneration
    DOI:  https://doi.org/10.3390/ijms25021125
  50. Front Cell Infect Microbiol. 2023 ;13 1324727
    Eliminating the invading extracellular and intracellular FnBp+ bacteria from respiratory epithelial cells by autophagy mediated through FnBp-Fn-Integrin α5β1 axis.
    Meiqi Meng, Jiachao Wang, Hongru Li, Jiao Wang, Xuan Wang, Miao Li, Xue Gao, Wenjian Li, Cuiqing Ma, Lin Wei.
      Background: We previously found that the respiratory epithelial cells could eliminate the invaded group A streptococcus (GAS) through autophagy induced by binding a fibronectin (Fn) binding protein (FnBp) expressed on the surface of GAS to plasma protein Fn and its receptor integrin α5β1 of epithelial cells. Is autophagy initiated by FnBp+ bacteria via FnBp-Fn-Integrin α5β1 axis a common event in respiratory epithelial cells?Methods: We chose Staphylococcus aureus (S. aureus/S. a) and Listeria monocytogenes (L. monocytogenes/L. m) as representatives of extracellular and intracellular FnBp+ bacteria, respectively. The FnBp of them was purified and the protein function was confirmed by western blot, viable bacteria count, confocal and pull-down. The key molecule downstream of the action axis was detected by IP, mass spectrometry and bio-informatics analysis.
    Results: We found that different FnBp from both S. aureus and L. monocytogenes could initiate autophagy through FnBp-Fn-integrin α5β1 axis and this could be considered a universal event, by which host tries to remove invading bacteria from epithelial cells. Importantly, we firstly reported that S100A8, as a key molecule downstream of integrin β1 chain, is highly expressed upon activation of integrin α5β1, which in turn up-regulates autophagy.
    Conclusions: Various FnBp from FnBp+ bacteria have the ability to initiate autophagy via FnBp-Fn-Integrin α5β1 axis to promote the removal of invading bacteria from epithelial cells in the presence of fewer invaders. S100A8 is a key molecule downstream of Integrin α5β1 in this autophagy pathway.
    Keywords:  FnBp; FnBp+ bacteria; Integrin α5β1; S100A8; autophagy
    DOI:  https://doi.org/10.3389/fcimb.2023.1324727
  51. Plant Physiol. 2024 Jan 19. pii: kiae026. [Epub ahead of print]
    Valsa mali effector Vm_04797 interacts with adaptor protein MdAP-2β to manipulate host autophagy.
    Yubo Sun, Danyan Luo, Yuerong Liu, Wenyan Tu, Runmin Che, Hao Feng, Lili Huang, Fengwang Ma, Changhai Liu.
      Apple Valsa canker, caused by the ascomycete fungus Valsa mali, employs virulence effectors to disturb host immunity and poses a substantialthreat to the apple industry. However, our understanding of how V. mali effectors regulate host defense responses remains limited. Here, we identified the V. mali effector Vm_04797, which was up-regulated during the early infection stage. Vm_04797, a secreted protein, suppressed Inverted formin 1 (INF1)-triggered cell death in Nicotiana benthamiana and performed virulence functions inside plant cells. Vm_04797 deletion mutants showed substantiallyreduced virulence towards apple. The adaptor protein MdAP-2β positively regulated apple Valsa canker resistance and was targeted and degraded by Vm_04797 via the ubiquitination pathway. The in vitro analysis suggested that Vm_04797 possesses E3 ubiquitin ligase activity. Further analysis revealed that MdAP-2β is involved in autophagy by interacting with Malus domestica autophagy protein 16 MdATG16 and promoting its accumulation. By degrading MdAP-2β, Vm_04797 inhibited autophagic flux, thereby disrupting the defense response mediated by autophagy. Our findings provide insights into the molecular mechanisms employed by the effectors of E3 ubiquitin ligase activity in ascomycete fungi to regulate host immunity.
    Keywords:   Valsa mali ; E3 ubiquitin ligase effector; adaptor protein; autophagy; degradation
    DOI:  https://doi.org/10.1093/plphys/kiae026
  52. EMBO Rep. 2024 Jan 23.
    Mitochondrial translocation of TFEB regulates complex I and inflammation.
    Chiara Calabrese, Hendrik Nolte, Melissa R Pitman, Raja Ganesan, Philipp Lampe, Raymond Laboy, Roberto Ripa, Julia Fischer, Ruhi Polara, Sameer Kumar Panda, Sandhya Chipurupalli, Saray Gutierrez, Daniel Thomas, Stuart M Pitson, Adam Antebi, Nirmal Robinson.
      TFEB is a master regulator of autophagy, lysosome biogenesis, mitochondrial metabolism, and immunity that works primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomics analysis reveals extensive TFEB co-immunoprecipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. High resolution confocal microscopy and biochemistry confirms TFEB localization in the mitochondrial matrix. TFEB translocation depends on a conserved N-terminal TOMM20-binding motif and is enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.
    Keywords:  LONP1; Metabolism; Mitochondria; Salmonella; TFEB
    DOI:  https://doi.org/10.1038/s44319-024-00058-0
  53. Brain Sci. 2024 Jan 19. pii: 96. [Epub ahead of print]14(1):
    Epigallocatechin-3-Gallate and Genistein for Decreasing Gut Dysbiosis, Inhibiting Inflammasomes, and Aiding Autophagy in Alzheimer's Disease.
    Ahalya Muraleedharan, Swapan K Ray.
      There are approximately 24 million cases of Alzheimer's disease (AD) worldwide, and the number of cases is expected to increase four-fold by 2050. AD is a neurodegenerative disease that leads to severe dementia in most patients. There are several neuropathological signs of AD, such as deposition of amyloid beta (Aβ) plaques, formation of neurofibrillary tangles (NFTs), neuronal loss, activation of inflammasomes, and declining autophagy. Several of these hallmarks are linked to the gut microbiome. The gastrointestinal (GI) tract contains microbial diversity, which is important in regulating several functions in the brain via the gut-brain axis (GBA). The disruption of the balance in the gut microbiota is known as gut dysbiosis. Recent studies strongly support that targeting gut dysbiosis with selective bioflavonoids is a highly plausible solution to attenuate activation of inflammasomes (contributing to neuroinflammation) and resume autophagy (a cellular mechanism for lysosomal degradation of the damaged components and recycling of building blocks) to stop AD pathogenesis. This review is focused on two bioflavonoids, specifically epigallocatechin-3-gallate (EGCG) and genistein (GS), as a possible new paradigm of treatment for maintaining healthy gut microbiota in AD due to their implications in modulating crucial AD signaling pathways. The combination of EGCG and GS has a higher potential than either agent alone to attenuate the signaling pathways implicated in AD pathogenesis. The effects of EGCG and GS on altering gut microbiota and GBA were also explored, along with conclusions from various delivery methods to increase the bioavailability of these bioflavonoids in the body.
    Keywords:  Alzheimer’s disease (AD); autophagy; bioflavonoids; epigallocatechin-3-gallate (EGCG); genistein (GS); gut dysbiosis; gut microbiome; inflammasomes
    DOI:  https://doi.org/10.3390/brainsci14010096
  54. Oncogenesis. 2024 Jan 25. 13(1): 6
    LUBAC promotes angiogenesis and lung tumorigenesis by ubiquitinating and antagonizing autophagic degradation of HIF1α.
    Ying Jin, Yazhi Peng, Jie Xu, Ye Yuan, Nan Yang, Zemei Zhang, Lei Xu, Lin Li, Yulian Xiong, Dejiao Sun, Yamu Pan, Ruiqing Wu, Jian Fu.
      Hypoxia-inducible factor 1 (HIF1) is critically important for driving angiogenesis and tumorigenesis. Linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin ligase capable of catalyzing protein linear ubiquitination to date, is implicated in cell signaling and associated with cancers. However, the role and mechanism of LUBAC in regulating the expression and function of HIF1α, the labile subunit of HIF1, remain to be elucidated. Herein we showed that LUBAC increases HIF1α protein expression in cultured cells and tissues of human lung cancer and enhances HIF1α DNA-binding and transcriptional activities, which are dependent upon LUBAC enzymatic activity. Mechanistically, LUBAC increases HIF1α stability through antagonizing HIF1α decay by the chaperone-mediated autophagy (CMA)-lysosome pathway, thereby potentiating HIF1α activity. We further demonstrated that HIF1α selectively interacts with HOIP (the catalytic subunit of LUBAC) primarily in the cytoplasm. LUBAC catalyzes linear ubiquitination of HIF1α at lysine 362. Linear ubiquitination shields HIF1α from interacting with heat-shock cognate protein of 70 kDa and lysosome-associated membrane protein type 2 A, two components of CMA. Consequently, linear ubiquitination confers protection against CMA-mediated destruction of HIF1α, increasing HIF1α stability and activity. We found that prolyl hydroxylation is not a perquisite for LUBAC's effects on HIF1α. Functionally, LUBAC facilitates proliferation, clonogenic formation, invasion and migration of lung cancer cells. LUBAC also boosts angiogenesis and exacerbates lung cancer growth in mice, which are greatly compromised by inhibition of HIF1α. This work provides novel mechanistic insights into the role of LUBAC in regulating HIF1α homeostasis, tumor angiogenesis and tumorigenesis of lung cancer, making LUBAC an attractive therapeutic target for cancers.
    DOI:  https://doi.org/10.1038/s41389-024-00508-3
  55. Cells. 2024 Jan 18. pii: 183. [Epub ahead of print]13(2):
    Autophagy and Apoptosis in Rabies Virus Replication.
    Saisai Li, Bowen Xu, Yongwen Luo, Jun Luo, Shile Huang, Xiaofeng Guo.
      Rabies virus (RABV) is a single-stranded negative-sense RNA virus belonging to the Rhabdoviridae family and Lyssavirus genus, which is highly neurotropic and can infect almost all warm-blooded animals, including humans. Autophagy and apoptosis are two evolutionarily conserved and genetically regulated processes that maintain cellular and organismal homeostasis, respectively. Autophagy recycles unnecessary or dysfunctional intracellular organelles and molecules in a cell, whereas apoptosis eliminates damaged or unwanted cells in an organism. Studies have shown that RABV can induce both autophagy and apoptosis in target cells. To advance our understanding of pathogenesis of rabies, this paper reviews the molecular mechanisms of autophagy and apoptosis induced by RABV and the effects of the two cellular events on RABV replication.
    Keywords:  apoptosis; autophagy; rabies virus; virus replication
    DOI:  https://doi.org/10.3390/cells13020183
  56. bioRxiv. 2024 Jan 01. pii: 2023.12.31.573735. [Epub ahead of print]
    Rapid turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation.
    Pei Yee Tey, Almut Dufner, Klaus-Peter Knobeloch, Jonathan N Pruneda, Michael J Clague, Sylvie Urbé.
      The immune checkpoint regulator CTLA4 is an unusually short-lived membrane protein. Here we show that its lysosomal degradation is dependent on ubiquitylation at Lysine residues 203 and 213. Inhibition of the v-ATPase partially restores CTLA4 levels following cycloheximide treatment, but also reveals a fraction that is secreted in exosomes. The endosomal deubiquitylase, USP8, interacts with CTLA4 and its loss enhances CTLA4 ubiquitylation in cancer cells, mouse CD4 + T cells and in cancer cell-derived exosomes. Depletion of the USP8 adapter protein, HD-PTP, but not ESCRT-0 recapitulates this cellular phenotype, but shows distinct properties vis-à-vis exosome incorporation. Re-expression of wild-type USP8, but neither a catalytically inactive, nor a localisation-compromised ΔMIT domain mutant can rescue delayed degradation of CTLA4, or counteract its accumulation in clustered endosomes. UbiCRest analysis of CTLA4-associated ubiquitin chain linkages identifies a complex mixture of conventional Lys63- and more unusual Lys27- and Lys29-linked polyubiquitin chains that may underly the rapidity of protein turnover.
    DOI:  https://doi.org/10.1101/2023.12.31.573735
  57. iScience. 2024 Jan 19. 27(1): 108777
    Rapamycin-sensitive mechanisms confine the growth of fission yeast below the temperatures detrimental to cell physiology.
    Yuichi Morozumi, Fontip Mahayot, Yukiko Nakase, Jia Xin Soong, Sayaka Yamawaki, Fajar Sofyantoro, Yuki Imabata, Arisa H Oda, Miki Tamura, Shunsuke Kofuji, Yutaka Akikusa, Ayu Shibatani, Kunihiro Ohta, Kazuhiro Shiozaki.
      Cells cease to proliferate above their growth-permissible temperatures, a ubiquitous phenomenon generally attributed to heat damage to cellular macromolecules. We here report that, in the presence of rapamycin, a potent inhibitor of Target of Rapamycin Complex 1 (TORC1), the fission yeast Schizosaccharomyces pombe can proliferate at high temperatures that usually arrest its growth. Consistently, mutations to the TORC1 subunit RAPTOR/Mip1 and the TORC1 substrate Sck1 significantly improve cellular heat resistance, suggesting that TORC1 restricts fission yeast growth at high temperatures. Aiming for a more comprehensive understanding of the negative regulation of high-temperature growth, we conducted genome-wide screens, which identified additional factors that suppress cell proliferation at high temperatures. Among them is Mks1, which is phosphorylated in a TORC1-dependent manner, forms a complex with the 14-3-3 protein Rad24, and suppresses the high-temperature growth independently of Sck1. Our study has uncovered unexpected mechanisms of growth restraint even below the temperatures deleterious to cell physiology.
    Keywords:  Biological sciences; Microbial physiology; Microbiology; Molecular microbiology
    DOI:  https://doi.org/10.1016/j.isci.2023.108777
  58. Int J Mol Sci. 2024 Jan 22. pii: 1324. [Epub ahead of print]25(2):
    Regulation of Benzo[a]pyrene-Induced Hepatic Lipid Accumulation through CYP1B1-Induced mTOR-Mediated Lipophagy.
    Kyung-Bin Bu, Min Kim, Min Kyoung Shin, Seung-Ho Lee, Jung-Suk Sung.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by lipid accumulation within the liver. The pathogenesis underlying its development is poorly understood. Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon and a group 1 carcinogen. The aryl hydrocarbon receptor activation by B[a]P induces cytochrome P450 (CYP) enzymes, contributing to hepatic lipid accumulation. However, the molecular mechanism through which the B[a]P-mediated induction of CYP enzymes causes hepatic lipid accumulation is unknown. This research was conducted to elucidate the role of CYP1B1 in regulating B[a]P-induced lipid accumulation within hepatocytes. B[a]P increased hepatic lipid accumulation, which was mitigated by CYP1B1 knockdown. An increase in the mammalian target of rapamycin (mTOR) by B[a]P was specifically reduced by CYP1B1 knockdown. The reduction of mTOR increased the expression of autophagic flux-related genes and promoted phagolysosome formation. Both the expression and translocation of TFE3, a central regulator of lipophagy, were induced, along with the expression of lipophagy-related genes. Conversely, enhanced mTOR activity reduced TFE3 expression and translocation, which reduced the expression of lipophagy-related genes, diminished phagolysosome production, and increased lipid accumulation. Our results indicate that B[a]P-induced hepatic lipid accumulation is caused by CYP1B1-induced mTOR and the reduction of lipophagy, thereby introducing novel targets and mechanisms to provide insights for understanding B[a]P-induced MASLD.
    Keywords:  CYP1B1; benzo[a]pyrene; lipophagy; mTOR; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.3390/ijms25021324
  59. J Biol Chem. 2024 Jan 23. pii: S0021-9258(24)00055-3. [Epub ahead of print] 105679
    Methyl vinyl ketone and its analogs covalently modify PI3K and alter physiological functions by inhibiting PI3K signaling.
    Atsushi Morimoto, Nobumasa Takasugi, Yuexuan Pan, Sho Kubota, Naoshi Dohmae, Yumi Abiko, Koji Uchida, Yoshito Kumagai, Takashi Uehara.
      Reactive carbonyl species (RCS), which are abundant in the environment and are produced in vivo under stress, covalently bind to nucleophilic residues such as cysteine (Cys) in proteins. Disruption of protein function by RCS exposure is predicted to play a role in the development of various diseases such as cancer and metabolic disorders, but most studies on RCS have been limited to simple cytotoxicity validation, leaving their target proteins and resulting physiological changes unknown. In this study, we focused on methyl vinyl ketone (MVK), which is one of the main RCS found in cigarette smoke and exhaust gas. We found that MVK suppressed phosphatidylinositol-3 kinase (PI3K)-Akt signaling, which regulates processes involved in cellular homeostasis, including cell proliferation, autophagy, and glucose metabolism. Interestingly, MVK inhibits the interaction between the epidermal growth factor (EGF) receptor and PI3K. Cys656 in the SH2 domain of the PI3K p85 subunit, which is the covalently binding site of MVK, is important for this interaction. Suppression of PI3K-Akt signaling by MVK reversed EGF-induced negative regulation of autophagy, and attenuated glucose uptake. Furthermore, we analyzed the effects of the 23 RCS compounds with structures similar to MVK and showed that their analogs also suppressed PI3K-Akt signaling in a manner that correlated with their similarities to MVK. Our study demonstrates the mechanism of MVK and its analogs in suppressing PI3K-Akt signaling and modulating physiological functions, providing a model for future studies analyzing environmental reactive species.
    Keywords:  autophagy; cell signaling; chemical modification; glucose uptake; phosphatidylinositol 3‐kinase (PI 3‐kinase)
    DOI:  https://doi.org/10.1016/j.jbc.2024.105679
  60. Aging (Albany NY). 2024 Jan 22. 15
    MicroRNA-141-3p reduces pulmonary hypoxia/reoxygenation injury through suppression of Beclin-1-dependent autophagy.
    Yanping Zhan, Lei Li, Chen Guo, Yang Zhang, Lili Zhao, Zhe Tao, Hua Zhang, Shibiao Chen.
      Alterations in autophagy are involved in pulmonary hypoxia/reoxygenation (H/R)-induced injury. Here, we intended to explain the function of microRNA-141-3p (miR-141-3p) in regulating autophagy under the H/R condition. Rat pulmonary microvascular endothelial cells (PMVECs) were applied for H/R cell model establishment, followed by tracing of autophagy formation. SIRT1 plays a critical role in controlling the lifespan of yeast, flies, and mice. Interaction between SIRT1 and Beclin-1, an indicator protein for autophagy, and between miR-141-3p and SIRT1 was assayed with their roles in PMVEC injury. Autophagy of PMVECs was activated after hypoxia treatment and further activated after H/R treatment. The binding of miR-141-3p and SIRT1 was verified. In H/R-treated PMVECs, the binding of miR-141-3p and SIRT1 was reduced. Furthermore, SIRT1 acted as a deacetylase to stabilize the Beclin-1 protein, promoting autophagy and PMVEC injury. H/R rat models were established, and in vivo, experiments further confirmed that miR-141-3p regulated autophagy and lung injury in H/R rats through SIRT1/Beclin-1 axis. The current study highlighted that reduced miR-141-3p in H/R-treated PMVECs promoted deacetylation of Beclin-1 by SIRT1, thus causing PMVEC injury.
    Keywords:  Beclin-1; SIRT1; autophagy; hypoxia/reoxygenation injury; microRNA-141-3p
    DOI:  https://doi.org/10.18632/aging.205430
  61. FEMS Microbiol Lett. 2024 Jan 09. pii: fnad121. [Epub ahead of print]371
    Effect of ATG8 or SAC1 deficiency on the cell proliferation and lifespan of the long-lived PMT1 deficiency yeast cells.
    Hongjing Cui, Xiaojing Cui, Xiaodi Yang, Xingang Cui, Yaxin Sun, Di Yuan, Qiong Cui, Yanwen Deng, Enhao Sun, Ya-Qin Chen, Hongsheng Guo, Ziliang Deng, Junfang Wang, Shun Xu, Xuerong Sun, Zhao Wei, Xinguang Liu.
      Autophagy is pivotal in maintaining intracellular homeostasis, which involves various biological processes, including cellular senescence and lifespan modulation. Being an important member of the protein O-mannosyltransferase (PMT) family of enzymes, Pmt1p deficiency can significantly extend the replicative lifespan (RLS) of yeast cells through an endoplasmic reticulum (ER) unfolded protein response (UPR) pathway, which is participated in protein homeostasis. Nevertheless, the mechanisms that Pmt1p regulates the lifespan of yeast cells still need to be explored. In this study, we found that the long-lived PMT1 deficiency strain (pmt1Δ) elevated the expression levels of most autophagy-related genes, the expression levels of total GFP-Atg8 fusion protein and free GFP protein compared with wild-type yeast strain (BY4742). Moreover, the long-lived pmt1Δ strain showed the greater dot-signal accumulation from GFP-Atg8 fusion protein in the vacuole lumen through a confocal microscope. However, deficiency of SAC1 or ATG8, two essential components of the autophagy process, decreased the cell proliferation ability of the long-lived pmt1Δ yeast cells, and prevented the lifespan extension. In addition, our findings demonstrated that overexpression of ATG8 had no potential effect on the RLS of the pmt1Δ yeast cells, and the maintained incubation of minimal synthetic medium lacking nitrogen (SD-N medium as starvation-induced autophagy) inhibited the cell proliferation ability of the pmt1Δ yeast cells with the culture time, and blocked the lifespan extension, especially in the SD-N medium cultured for 15 days. Our results suggest that the long-lived pmt1Δ strain enhances the basal autophagy activity, while deficiency of SAC1 or ATG8 decreases the cell proliferation ability and shortens the RLS of the long-lived pmt1Δ yeast cells. Moreover, the maintained starvation-induced autophagy impairs extension of the long-lived pmt1Δ yeast cells, and even leads to the cell death.
    Keywords:   Saccharomyces cerevisiae ; ageing; autophagy; protein O-mannosyltransferase; replicative lifespan
    DOI:  https://doi.org/10.1093/femsle/fnad121
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