bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023‒03‒05
53 papers selected by
Viktor Korolchuk, Newcastle University
  1. LAMTOR1 ubiquitination restricts its interaction with the vacuolar-type H+-ATPase, promotes autophagy and is controlled by USP32.
  2. The interplay between selective types of (macro)autophagy: Mitophagy and xenophagy.
  3. Non-muscle MYH10/myosin IIB recruits ESCRT-III to participate in autophagosome closure to maintain neuronal homeostasis.
  4. Autophagy and kidney aging.
  5. Autophagy regulates plastid reorganization during spermatogenesis in the liverwort Marchantia polymorpha.
  6. Autophagy and autophagy-related pathways in cancer.
  7. Is Disrupted Mitophagy a Central Player to Parkinson's Disease Pathology?
  8. Crosstalk between endoplasmic reticulum stress response and autophagy in human diseases.
  9. L-type amino acid transporter 1 in hypothalamic neurons in mice maintains energy and bone homeostasis.
  10. MTORC2 is a physiological hydrophobic motif kinase of S6 Kinase 1.
  11. Autophagy in the retinal neurovascular unit: New perspectives into diabetic retinopathy.
  12. MYTHO is a novel regulator of skeletal muscle autophagy and integrity.
  13. The role of autophagy in bone metabolism and clinical significance.
  14. Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress.
  15. The Emerging Role of Autophagy as a Target of Environmental Pollutants: An Update on Mechanisms.
  16. ATG16L1 adopts a dual-binding site mode to interact with WIPI2b in autophagy.
  17. Chronic neuronal inactivity utilizes the mTOR-TFEB pathway to drive transcription-dependent autophagy for homeostatic up-scaling.
  18. Lysosomal control of senescence and inflammation through cholesterol partitioning.
  19. Sestrin2: multifaceted functions, molecular basis, and its implications in liver diseases.
  20. N protein of PEDV plays chess game with host proteins by selective autophagy.
  21. The inflammation repressor TNIP1/ABIN-1 is degraded by autophagy following TBK1 phosphorylation of its LIR.
  22. Mucus secretion from colonic goblet cells is regulated by autophagy and ER stress.
  23. AlphaFold-multimer predicts ATG8 protein binding motifs crucial for autophagy research.
  24. FPR1 is essential for rapamycin-induced lifespan extension in Saccharomyces cerevisiae.
  25. Multi-modal Proteomic Characterization of Lysosomal Function and Proteostasis in Progranulin-Deficient Neurons.
  26. BNIP3-mediated autophagy via the mTOR/ULK1 pathway induces primordial follicle loss after ovarian tissue transplantation.
  27. UBE3A deficiency-induced autophagy is associated with activation of AMPK-ULK1 and p53 pathways.
  28. Formosanin C suppresses cancer cell proliferation and migration by impeding autophagy machinery.
  29. Autophagy dysregulation in trichloroethene-mediated inflammation and autoimmune response.
  30. Autophagy-dependent ferroptosis as a potential treatment for glioblastoma.
  31. K63-linked ubiquitin chains are a global signal for endocytosis and contribute to selective autophagy in plants.
  32. A novel combination of isovanillin, curcumin, and harmine (GZ17-6.02) enhances cell death and alters signaling in actinic keratoses cells when compared to individual components and two-component combinations.
  33. Mitophagy and Traumatic Brain Injury: Regulatory Mechanisms and Therapeutic Potentials.
  34. HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies.
  35. Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson's disease GBA-N370S dopamine neurons.
  36. Molecular mechanisms of cancer cachexia-related loss of skeletal muscle mass: data analysis from preclinical and clinical studies.
  37. Systematic Transmission Electron Microscopy-Based Identification and 3D Reconstruction of Cellular Degradation Machinery.
  38. Euphejolkinolide A, a new ent-abietane lactone from Euphorbia peplus L. with promising biological activity in activating the autophagy-lysosomal pathway.
  39. Biological functions and structural biology of Plasmodium falciparum autophagy-related proteins: the under-explored options for novel antimalarial drug design.
  40. ACKR4a induces autophagy to block NF-κB signaling and apoptosis to facilitate Vibrio harveyi infection.
  41. Quantification of autophagy flux in isolated mouse skeletal muscle fibers with overexpression of fluorescent protein mCherry-EGFP-LC3.
  42. Intestinal epithelial autophagy is required for the regenerative benefit of calorie restriction.
  43. MAEL facilitates metabolic reprogramming and breast cancer progression by promoting the degradation of citrate synthase and fumarate hydratase via chaperone-mediated autophagy.
  44. l-Asparaginase regulates mTORC1 activity via a TSC2-dependent pathway in pancreatic beta cells.
  45. An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets.
  46. Autophagy and Alzheimer's disease: How far science has to be progressed? - correspondence.
  47. Mitochondrial Hydrogen Peroxide Activates PTEN and Inactivates Akt Leading to Autophagy Inhibition-Dependent Cell Death in Neuronal Models of Parkinson's Disease.
  48. mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion.
  49. Saturated fatty acids increase LPI to reduce FUNDC1 dimerization and stability and mitochondrial function.
  50. StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival.
  51. Endolysosomal impairment by binding of amyloid beta or MAPT/Tau to V-ATPase and rescue via the HYAL-CD44 axis in Alzheimer disease.
  52. Cell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis.
  53. Proteostasis and Ribostasis Impairment as Common Cell Death Mechanisms in Neurodegenerative Diseases.
  1. Autophagy. 2023 Mar 01. 1-2
    LAMTOR1 ubiquitination restricts its interaction with the vacuolar-type H+-ATPase, promotes autophagy and is controlled by USP32.
    Alexandra Hertel, Stefan Eimer, Anja Bremm.
      Among the various signals governing autophagy, ubiquitination plays a critical role both by controlling the stability of upstream regulators or components of macroautophagy/autophagy pathways and by facilitating the recruitment of cargo to autophagy receptors. As such, modulators of ubiquitin signaling can influence autophagic substrate degradation. Recently, we identified a non-proteolytic ubiquitin signal at the Ragulator complex subunit LAMTOR1 that is reversed by the deubiquitinase USP32. Loss of USP32 promotes ubiquitination within the unstructured N-terminal region of LAMTOR1 and prevents its efficient interaction with the vacuolar-type H+-ATPase, a prerequisite for full activation of MTORC1 at lysosomes. Consequently, MTORC1 activity is decreased and autophagy is upregulated in USP32 knockout cells. This phenotype is conserved in Caenorhabditis elegans. Depletion of USP32 homolog CYK-3 in worms results in LET-363/MTOR inhibition and autophagy induction. Based on our data, we propose an additional control layer of the MTORC1 activation cascade at lysosomes via USP32-regulated LAMTOR1 ubiquitination.
    Keywords:  ATPase; LAMTOR1; USP32; V-MTORC1; autophagy; deubiquitinase (DUB); ragulator complex; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2023.2184958
  2. Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(22)00137-X. [Epub ahead of print]374 129-157
    The interplay between selective types of (macro)autophagy: Mitophagy and xenophagy.
    Teresa Rubio-Tomás, Aggeliki Sotiriou, Nektarios Tavernarakis.
      Autophagy is a physiological response, activated by a myriad of endogenous and exogenous cues, including DNA damage, perturbation of proteostasis, depletion of nutrients or oxygen and pathogen infection. Upon sensing those stimuli, cells employ multiple non-selective and selective autophagy pathways to promote fitness and survival. Importantly, there are a variety of selective types of autophagy. In this review we will focus on autophagy of bacteria (xenophagy) and autophagy of mitochondria (mitophagy). We provide a brief introduction to bulk autophagy, as well as xenophagy and mitophagy, highlighting their common molecular factors. We also describe the role of xenophagy and mitophagy in the detection and elimination of pathogens by the immune system and the adaptive mechanisms that some pathogens have developed through evolution to escape the host autophagic response. Finally, we summarize the recent articles (from the last five years) linking bulk autophagy with xenophagy and/or mitophagy in the context on developmental biology, cancer and metabolism.
    Keywords:  (Macro)autophagy; Cancer; Development; Metabolism; Mitophagy; Pathogens; Xenophagy
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.10.003
  3. Autophagy. 2023 Feb 27. 1-17
    Non-muscle MYH10/myosin IIB recruits ESCRT-III to participate in autophagosome closure to maintain neuronal homeostasis.
    Yong-Woo Jun, Soojin Lee, Byung-Kwan Ban, Jin-A Lee, Fen-Biao Gao.
      Dysfunction of the endosomal sorting complex required for transport (ESCRT) has been linked to frontotemporal dementia (FTD) due in part to the accumulation of unsealed autophagosomes. However, the mechanisms of ESCRT-mediated membrane closure events on phagophores remain largely unknown. In this study, we found that partial knockdown of non-muscle MYH10/myosin IIB/zip rescues neurodegeneration in both Drosophila and human iPSC-derived cortical neurons expressing FTD-associated mutant CHMP2B, a subunit of ESCRT-III. We also found that MYH10 binds and recruits several autophagy receptor proteins during autophagosome formation induced by mutant CHMP2B or nutrient starvation. Moreover, MYH10 interacted with ESCRT-III to regulate phagophore closure by recruiting ESCRT-III to damaged mitochondria during PRKN/parkin-mediated mitophagy. Evidently, MYH10 is involved in the initiation of induced but not basal autophagy and also links ESCRT-III to mitophagosome sealing, revealing novel roles of MYH10 in the autophagy pathway and in ESCRT-related FTD pathogenesis.Abbreviations: ALS: amyotrophic lateral sclerosis; AP: autophagosome; Atg: autophagy-related; ESCRT: endosomal sorting complex required for transport; FTD: frontotemporal dementia.
    Keywords:  Autophagy; Drosophila; ESCRT; mitophagy; myosin II; neurodegeneration; neuron
    DOI:  https://doi.org/10.1080/15548627.2023.2169309
  4. Prog Biophys Mol Biol. 2023 Feb 25. pii: S0079-6107(23)00017-2. [Epub ahead of print]
    Autophagy and kidney aging.
    Satoshi Minami, Takeshi Yamamoto, Hitomi Yamamoto-Imoto, Yoshitaka Isaka, Maho Hamasaki.
      Autophagy is a highly conserved intracellular degradation system in eukaryotes that contributes to maintaining cellular and tissue homeostasis. Upon autophagy induction, cytoplasmic components are engulfed by a double-membrane organelle called the autophagosome that fuses with a lysosome to degrade its contents. In recent years, it has become clear that autophagy becomes dysregulated with aging, which leads to age-related diseases. Kidney function is particularly prone to age-related decline, and aging is the greatest risk factor for chronic kidney disease. In this review, we first discuss the relationship between autophagy and kidney aging. Second, we describe how age-related dysregulation of autophagy occurs. Finally, we discuss the potential of autophagy-targeting drugs to ameliorate human kidney aging and the approaches necessary to facilitate the discovery of such agents. Contents.
    Keywords:  Autophagy; Chronic kidney disease; Kidney aging; Lysosome
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2023.02.005
  5. Front Plant Sci. 2023 ;14 1101983
    Autophagy regulates plastid reorganization during spermatogenesis in the liverwort Marchantia polymorpha.
    Takuya Norizuki, Naoki Minamino, Miyuki Sato, Takashi Ueda.
      Autophagy is a highly conserved system that delivers cytoplasmic components to lysosomes/vacuoles. Plastids are also degraded through autophagy for nutrient recycling and quality control; however, the involvement of autophagic degradation of plastids in plant cellular differentiation remains unclear. Here, we investigated whether spermiogenesis, the differentiation of spermatids into spermatozoids, in the liverwort Marchantia polymorpha involves autophagic degradation of plastids. Spermatozoids of M. polymorpha possess one cylindrical plastid at the posterior end of the cell body. By fluorescently labeling and visualizing plastids, we detected dynamic morphological changes during spermiogenesis. We found that a portion of the plastid was degraded in the vacuole in an autophagy-dependent manner during spermiogenesis, and impaired autophagy resulted in defective morphological transformation and starch accumulation in the plastid. Furthermore, we found that autophagy was dispensable for the reduction in plastid number and plastid DNA elimination. These results demonstrate a critical but selective role of autophagy in plastid reorganization during spermiogenesis in M. polymorpha.
    Keywords:  Marchantia polymorpha; autophagy; plastid; plastid DNA; spermatid; spermatozoid; spermiogenesis
    DOI:  https://doi.org/10.3389/fpls.2023.1101983
  6. Nat Rev Mol Cell Biol. 2023 Mar 02.
    Autophagy and autophagy-related pathways in cancer.
    Jayanta Debnath, Noor Gammoh, Kevin M Ryan.
      Maintenance of protein homeostasis and organelle integrity and function is critical for cellular homeostasis and cell viability. Autophagy is the principal mechanism that mediates the delivery of various cellular cargoes to lysosomes for degradation and recycling. A myriad of studies demonstrate important protective roles for autophagy against disease. However, in cancer, seemingly opposing roles of autophagy are observed in the prevention of early tumour development versus the maintenance and metabolic adaptation of established and metastasizing tumours. Recent studies have addressed not only the tumour cell intrinsic functions of autophagy, but also the roles of autophagy in the tumour microenvironment and associated immune cells. In addition, various autophagy-related pathways have been described, which are distinct from classical autophagy, that utilize parts of the autophagic machinery and can potentially contribute to malignant disease. Growing evidence on how autophagy and related processes affect cancer development and progression has helped guide efforts to design anticancer treatments based on inhibition or promotion of autophagy. In this Review, we discuss and dissect these different functions of autophagy and autophagy-related processes during tumour development, maintenance and progression. We outline recent findings regarding the role of these processes in both the tumour cells and the tumour microenvironment and describe advances in therapy aimed at autophagy processes in cancer.
    DOI:  https://doi.org/10.1038/s41580-023-00585-z
  7. Cureus. 2023 Feb;15(2): e35458
    Is Disrupted Mitophagy a Central Player to Parkinson's Disease Pathology?
    Tsz Ki Ko, Denise Jia Yun Tan.
      Whilst the pathophysiology at a cellular level has been defined, the cause of Parkinson's disease (PD) remains poorly understood. This neurodegenerative disorder is associated with impaired dopamine transmission in the substantia nigra, and protein accumulations known as Lewy bodies are visible in affected neurons. Cell culture models of PD have indicated impaired mitochondrial function, so the focus of this paper is on the quality control processes involved in and around mitochondria. Mitochondrial autophagy (mitophagy) is the process through which defective mitochondria are removed from the cell by internalisation into autophagosomes which fuse with a lysosome. This process involves many proteins, notably including PINK1 and parkin, both of which are known to be coded on genes associated with PD. Normally in healthy individuals, PINK1 associates with the outer mitochondrial membrane, which then recruits parkin, activating it to attach ubiquitin proteins to the mitochondrial membrane. PINK1, parkin, and ubiquitin cooperate to form a positive feedback system which accelerates the deposition of ubiquitin on dysfunctional mitochondria, resulting in mitophagy. However, in hereditary PD, the genes encoding PINK1 and parkin are mutated, resulting in proteins that are less efficient at removing poorly performing mitochondria, leaving cells more vulnerable to oxidative stress and ubiquitinated inclusion bodies, such as Lewy bodies. Current research that looks into the connection between mitophagy and PD is promising, already yielding potentially therapeutic compounds; until now, pharmacological support for the mitophagy process has not been part of the therapeutic arsenal. Continued research in this area is warranted.
    Keywords:  lewy body; mitophagy; parkin; parkinson's disease; pink1
    DOI:  https://doi.org/10.7759/cureus.35458
  8. Anim Cells Syst (Seoul). 2023 ;27(1): 29-37
    Crosstalk between endoplasmic reticulum stress response and autophagy in human diseases.
    Junhee Kwon, Jihyun Kim, Keun Il Kim.
      Cells activate protective mechanisms to overcome stressful conditions that threaten cellular homeostasis, including imbalances in calcium, redox, and nutrient levels. Endoplasmic reticulum (ER) stress activates an intracellular signaling pathway, known as the unfolded protein response (UPR), to mitigate such circumstances and protect cells. Although ER stress is sometimes a negative regulator of autophagy, UPR induced by ER stress typically activates autophagy, a self-degradative pathway that further supports its cytoprotective role. Sustained activation of ER stress and autophagy is known to trigger cell death and is considered a therapeutic target for certain diseases. However, ER stress-induced autophagy can also lead to treatment resistance in cancer and exacerbation of certain diseases. Since the ER stress response and autophagy affect each other, and the degree of their activation is closely related to various diseases, understanding their relationship is very important. In this review, we summarize the current understanding of two fundamental cellular stress responses, the ER stress response and autophagy, and their crosstalk under pathological conditions to help develop therapies for inflammatory diseases, neurodegenerative disorders, and cancer.
    Keywords:  Endoplasmic reticulum (ER) stress; autophagy; human diseases; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1080/19768354.2023.2181217
  9. JCI Insight. 2023 Mar 02. pii: e154925. [Epub ahead of print]
    L-type amino acid transporter 1 in hypothalamic neurons in mice maintains energy and bone homeostasis.
    Gyujin Park, Kazuya Fukasawa, Tetsuhiro Horie, Yusuke Masuo, Yuka Inaba, Takanori Tatsuno, Takanori Yamada, Kazuya Tokumura, Sayuki Iwahashi, Takashi Iezaki, Katsuyuki Kaneda, Yukio Kato, Yasuhito Ishigaki, Michihiro Mieda, Tomohiro Tanaka, Kazuma Ogawa, Hiroki Ochi, Shingo Sato, Yun-Bo Shi, Hiroshi Inoue, Hojoon Lee, Eiichi Hinoi.
      Hypothalamic neurons regulate body homeostasis by sensing and integrating changes in the levels of key hormones and primary nutrients (amino acids, glucose, and lipids). However, the molecular mechanisms that enable hypothalamic neurons to detect primary nutrients remain elusive. Here, we identified L-type amino acid transporter 1 (LAT1) in hypothalamic leptin receptor (LepR)-expressing neurons as being important for systemic energy and bone homeostasis. We observed LAT1-dependent amino acid uptake in the hypothalamus, which was compromised in a mouse model of obesity and diabetes. Mice lacking LAT1 (encoded by Slc7a5) in LepR-expressing neurons exhibited obesity-related phenotypes and higher bone mass. Slc7a5 deficiency caused sympathetic dysfunction and leptin insensitivity in LepR-expressing neurons before obesity onset. Importantly, restoring Slc7a5 expression selectively in LepR-expressing ventromedial hypothalamus neurons rescued energy and bone homeostasis in mice deficient for Slc7a5 in LepR-expressing cells. Mechanistic target of rapamycin complex-1 (mTORC1) was found to be a crucial mediator of LAT1-dependent regulation of energy and bone homeostasis. These results suggest that the LAT1-mTORC1 axis in LepR-expressing neurons controls energy and bone homeostasis by fine-tuning sympathetic outflow, thus providing in vivo evidence of the implications of amino acid sensing by hypothalamic neurons in body homeostasis.
    Keywords:  Amino acid metabolism; Bone Biology; Bone disease; Endocrinology; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.154925
  10. Biochim Biophys Acta Mol Cell Res. 2023 Feb 28. pii: S0167-4889(23)00020-4. [Epub ahead of print]1870(4): 119449
    MTORC2 is a physiological hydrophobic motif kinase of S6 Kinase 1.
    Sheikh Tahir Majeed, Rabiya Majeed, Aijaz A Malik, Khurshid Iqbal Andrabi.
      Ribosomal protein S6 kinase 1 (S6K1), a major downstream effector molecule of mTORC1, regulates cell growth and proliferation by modulating protein translation and ribosome biogenesis. We have recently identified eIF4E as an intermediate in transducing signals from mTORC1 to S6K1 and further demonstrated that the role of mTORC1 is restricted to inducing eIF4E phosphorylation and interaction with S6K1. This interaction relieves S6K1 auto-inhibition and facilitates its hydrophobic motif (HM) phosphorylation and activation as a consequence. These observations underscore a possible involvement of mTORC1 independent kinase in mediating HM phosphorylation. Here, we report mTORC2 as an in-vivo/physiological HM kinase of S6K1. We show that rapamycin-resistant S6K1 truncation mutant ∆NH∆CT continues to display HM phosphorylation with selective sensitivity toward Torin-1. We also show that HM phosphorylation of wildtype S6K1and ∆NH∆CT depends on the presence of mTORC2 regulatory subunit-rictor. Furthermore, truncation mutagenesis and molecular docking analysis reveal the involvement of a conserved 19 amino acid stretch of S6K1 in mediating interaction with rictor. We finally show that deletion of the 19 amino acid region from wildtype S6K1 results in loss of interaction with rictor, with a resultant loss of HM phosphorylation regardless of the presence of functional TOS motif. Our data demonstrate that mTORC2 acts as a physiological HM kinase that can activate S6K1 after its auto-inhibition is overcome by mTORC1. We, therefore, propose a novel mechanism for S6K1 regulation where mTOR complexes 1 and 2 act in tandem to activate the enzyme.
    Keywords:  Hydrophobic motif; Kinase; Rapamycin; S6 Kinase 1; Torin; eIF4E; mTORC1; mTORC2
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119449
  11. J Diabetes. 2023 Mar 02.
    Autophagy in the retinal neurovascular unit: New perspectives into diabetic retinopathy.
    Xiongyi Yang, Zexin Huang, Mei Xu, Yanxia Chen, Mingzhe Cao, Guoguo Yi, Min Fu.
      Diabetic retinopathy (DR) is one of the most prevalent retinal disorders worldwide, and it is a major cause of vision impairment in individuals of productive age. Research has demonstrated the significance of autophagy in DR, which is a critical intracellular homeostasis mechanism required for the destruction and recovery of cytoplasmic components. Autophagy maintains the physiological function of senescent and impaired organelles under stress situations, thereby regulating cell fate via various signals. As the retina's functional and fundamental unit, the retinal neurovascular unit (NVU) is critical in keeping the retinal environment's stability and supporting the needs of retinal metabolism. However, autophagy is essential for the normal NVU structure and function. We discuss the strong association between DR and autophagy in this review, as well as the many kinds of autophagy and its crucial physiological activities in the retina. By evaluating the pathological changes of retinal NVU in DR and the latest advancements in the molecular mechanisms of autophagy that may be involved in the pathophysiology of DR in NVU, we seek to propose new ideas and methods for the prevention and treatment of DR.
    Keywords:  autophagy; diabetic retinopathy; mitophagy; retinal neurovascular unit
    DOI:  https://doi.org/10.1111/1753-0407.13373
  12. Nat Commun. 2023 Mar 02. 14(1): 1199
    MYTHO is a novel regulator of skeletal muscle autophagy and integrity.
    Jean-Philippe Leduc-Gaudet, Anais Franco-Romero, Marina Cefis, Alaa Moamer, Felipe E Broering, Giulia Milan, Roberta Sartori, Tomer Jordi Chaffer, Maude Dulac, Vincent Marcangeli, Dominique Mayaki, Laurent Huck, Anwar Shams, José A Morais, Elise Duchesne, Hanns Lochmuller, Marco Sandri, Sabah N A Hussain, Gilles Gouspillou.
      Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.
    DOI:  https://doi.org/10.1038/s41467-023-36817-1
  13. Autophagy. 2023 Mar 01.
    The role of autophagy in bone metabolism and clinical significance.
    Jing Wang, Yi Zhang, Jin Cao, Yi Wang, Nadia Anwar, Zihan Zhang, Dingmei Zhang, Yaping Ma, Yin Xiao, Lan Xiao, Xin Wang.
      The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions, supplies places to the hematopoietic system, and participates in complex endocrine and immune system. Not surprisingly, bones are constantly reabsorbed, formed, and remodeled under physiological conditions. Once bone metabolic homeostasis is interrupted (including inflammation, tumors, fractures, and bone metabolic diseases), the body rapidly initiates bone regeneration to maintain bone tissue structure and quality. Macroautophagy/autophagy is an essential metabolic process in eukaryotic cells, which maintains metabolic energy homeostasis and plays a vital role in bone regeneration by controlling molecular degradation and organelle renewal. One relatively new observation is that mesenchymal cells, osteoblasts, osteoclasts, osteocytes, chondrocytes, and vascularization process exhibit autophagy, and the molecular mechanisms and targets involved are being explored and updated. The role of autophagy is also emerging in degenerative diseases (intervertebral disc degeneration [IVDD], osteoarthritis [OA], etc.) and bone metabolic diseases (osteoporosis [OP], osteitis deformans, osteosclerosis). The use of autophagy regulators to modulate autophagy has benefited bone regeneration, including MTOR (mechanistic target of rapamycin kinase) inhibitors, AMPK activators, and emerging phytochemicals. The application of biomaterials (especially nanomaterials) to trigger autophagy is also an attractive research direction, which can exert superior therapeutic properties from the material-loaded molecules/drugs or the material's properties such as shape, roughness, surface chemistry, etc. All of these have essential clinical significance with the discovery of autophagy associated signals, pathways, mechanisms, and treatments in bone diseases in the future.
    Keywords:  autophagy; bone metabolism; mesenchymal stem cell; osteoblast; osteoclast; osteogenesis; osteoporosis; senescence
    DOI:  https://doi.org/10.1080/15548627.2023.2186112
  14. Phytomedicine. 2023 Feb 18. pii: S0944-7113(23)00078-8. [Epub ahead of print]112 154720
    Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress.
    Zhenpeng Niu, Guihua Tang, Xuenan Wang, Xu Yang, Yueqin Zhao, Yinyuan Wang, Qin Liu, Fan Zhang, Yuhan Zhao, Xiao Ding, Xiaojiang Hao.
      BACKGROUND: Macroautophagy (henceforth autophagy) is the major form of autophagy, which delivers intracellular cargo to lysosomes for degradation. Considerable research has revealed that the impairment of lysosomal biogenesis and autophagic flux exacerbates the development of autophagy-related diseases. Therefore, reparative medicines restoring lysosomal biogenesis and autophagic flux in cells may have therapeutic potential against the increasing prevalence of these diseases.PURPOSE: The aim of the present study was thus to explore the effect of trigonochinene E (TE), an aromatic tetranorditerpene isolated from Trigonostemon flavidus, on lysosomal biogenesis and autophagy and to elucidate the potential underlying mechanism.
    METHODS: Four human cell lines, HepG2, nucleus pulposus (NP), HeLa and HEK293 cells were applied in this study. The cytotoxicity of TE was evaluated by MTT assay. Lysosomal biogenesis and autophagic flux induced by 40 μM TE were analyzed using gene transfer techniques, western blotting, real-time PCR and confocal microscopy. Immunofluorescence, immunoblotting and pharmacological inhibitors/activators were applied to determine the changes in the protein expression levels in mTOR, PKC, PERK, and IRE1α signaling pathways.
    RESULTS: Our results showed that TE promotes lysosomal biogenesis and autophagic flux by activating the transcription factors of lysosomes, transcription factor EB (TFEB) and transcription factor E3 (TFE3). Mechanistically, TE induces TFEB and TFE3 nuclear translocation through an mTOR/PKC/ROS-independent and endoplasmic reticulum (ER) stress-mediated pathway. The PERK and IRE1α branches of ER stress are crucial for TE-induced autophagy and lysosomal biogenesis. Whereas TE activated PERK, which mediated calcineurin dephosphorylation of TFEB/TFE3, IRE1α was activated and led to inactivation of STAT3, which further enhanced autophagy and lysosomal biogenesis. Functionally, knockdown of TFEB or TFE3 impairs TE-induced lysosomal biogenesis and autophagic flux. Furthermore, TE-induced autophagy protects NP cells from oxidative stress to ameliorate intervertebral disc degeneration (IVDD).
    CONCLUSIONS: Here, our study showed that TE can induce TFEB/TFE3-dependent lysosomal biogenesis and autophagy via the PERK-calcineurin axis and IRE1α-STAT3 axis. Unlike other agents regulating lysosomal biogenesis and autophagy, TE showed limited cytotoxicity, thereby providing a new direction for therapeutic opportunities to use TE to treat diseases with impaired autophagy-lysosomal pathways, including IVDD.
    Keywords:  Autophagy; ER stress; IVDD; Lysosomal biogenesis; TFEB/TFE3
    DOI:  https://doi.org/10.1016/j.phymed.2023.154720
  15. Toxics. 2023 Jan 30. pii: 135. [Epub ahead of print]11(2):
    The Emerging Role of Autophagy as a Target of Environmental Pollutants: An Update on Mechanisms.
    Md Ataur Rahman, Md Saidur Rahman, Md Anowar Khasru Parvez, Bonglee Kim.
      Autophagy is an evolutionarily conserved cellular system crucial for cellular homeostasis that protects cells from a broad range of internal and extracellular stresses. Autophagy decreases metabolic load and toxicity by removing damaged cellular components. Environmental contaminants, particularly industrial substances, can influence autophagic flux by enhancing it as a protective response, preventing it, or converting its protective function into a pro-cell death mechanism. Environmental toxic materials are also notorious for their tendency to bioaccumulate and induce pathophysiological vulnerability. Many environmental pollutants have been found to influence stress which increases autophagy. Increasing autophagy was recently shown to improve stress resistance and reduce genetic damage. Moreover, suppressing autophagy or depleting its resources either increases or decreases toxicity, depending on the circumstances. The essential process of selective autophagy is utilized by mammalian cells in order to eliminate particulate matter, nanoparticles, toxic metals, and smoke exposure without inflicting damage on cytosolic components. Moreover, cigarette smoke and aging are the chief causes of chronic obstructive pulmonary disease (COPD)-emphysema; however, the disease's molecular mechanism is poorly known. Therefore, understanding the impacts of environmental exposure via autophagy offers new approaches for risk assessment, protection, and preventative actions which will counter the harmful effects of environmental contaminants on human and animal health.
    Keywords:  autophagosome; autophagy; environmental exposure; nanoparticles; particulate matter; pesticides; toxic materials
    DOI:  https://doi.org/10.3390/toxics11020135
  16. Sci Adv. 2023 Mar;9(9): eadf0824
    ATG16L1 adopts a dual-binding site mode to interact with WIPI2b in autophagy.
    Xinyu Gong, Yingli Wang, Yubin Tang, Yaru Wang, Mingfang Zhang, Miao Li, Yuchao Zhang, Lifeng Pan.
      Macroautophagy plays crucial roles in the regulation of cellular physiology and requires de novo synthesis of double-membrane autophagosomes, which relies on a specific interaction between autophagy-related 16L1 (ATG16L1) and WD repeat domain phosphoinositide-interacting protein 2b (WIPI2b). However, the molecular mechanism governing the interaction of ATG16L1 with WIPI2b remains elusive. Here, we find that ATG16L1 has two distinct binding sites for interacting with WIPI2b, the previously reported WIPI2b-binding site (WBS1) and the previously unidentified site (WBS2). We determine the crystal structures of WIPI2b with ATG16L1 WBS1 and WBS2, respectively, and elucidate the molecular mechanism underpinning the recruitment of ATG16L1 by WIPI2b. Moreover, we uncover that ATG16L1 WBS2 and its binding mode with WIPI2b is well conserved from yeast to mammals, unlike ATG16L1 WBS1. Last, our cell-based functional assays demonstrate that both ATG16L1 WBS1 and WBS2 are required for the effective autophagic flux. In conclusion, our findings provide mechanistic insights into the key ATG16L1/WIPI2b interaction in autophagy.
    DOI:  https://doi.org/10.1126/sciadv.adf0824
  17. J Neurosci. 2023 Mar 02. pii: JN-RM-0146-23. [Epub ahead of print]
    Chronic neuronal inactivity utilizes the mTOR-TFEB pathway to drive transcription-dependent autophagy for homeostatic up-scaling.
    Yang Wang, Jingran Lin, Jiarui Li, Lu Yan, Wenwen Li, Xingzhi He, Huan Ma.
      Activity-dependent changes in protein expression are critical for neuronal plasticity, a fundamental process for the processing and storage of information in the brain. Among the various forms of plasticity, homeostatic synaptic up-scaling is unique in that it is induced primarily by neuronal inactivity. However, precisely how the turnover of synaptic proteins occurs in this homeostatic process remains unclear. Here, we report that chronically inhibiting neuronal activity in primary cortical neurons prepared from E18 Sprague-Dawley rats (both sexes) induces autophagy, thereby regulating key synaptic proteins for up-scaling. Mechanistically, chronic neuronal inactivity causes dephosphorylation of ERK and mTOR, which induces TFEB-mediated cytonuclear signaling and drives transcription-dependent autophagy to regulate αCaMKII and PSD95 during synaptic up-scaling. Together, these findings suggest that mTOR-dependent autophagy, which is often triggered by metabolic stressors such as starvation, is recruited and sustained during neuronal inactivity in order to maintain synaptic homeostasis, a process that ensures proper brain function and if impaired can cause neuropsychiatric disorders such as autism.SIGNIFICANCE STATEMENT:In the mammalian brain, protein turnover is tightly controlled by neuronal activation to ensure key neuronal functions during long-lasting synaptic plasticity. However, a long-standing question is how this process occurs during synaptic up-scaling, a process that requires protein turnover but is induced by neuronal inactivation. Here, we report that mTOR-dependent signaling-which is often triggered by metabolic stressors such as starvation-is "hijacked" by chronic neuronal inactivation, which then serves as a nucleation point for TFEB cytonuclear signaling that drives transcription-dependent autophagy for up-scaling. These results provide the first evidence of a physiological role of mTOR-dependent autophagy in enduing neuronal plasticity, thereby connecting major themes in cell biology and neuroscience via a servo loop that mediates autoregulation in the brain.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0146-23.2023
  18. Nat Metab. 2023 Mar 02.
    Lysosomal control of senescence and inflammation through cholesterol partitioning.
    Kyeonghwan Roh, Jeonghwan Noh, Yeonju Kim, Yeji Jang, Jaejin Kim, Haebeen Choi, Yeonghyeon Lee, Moongi Ji, Donghyun Kang, Mi-Sung Kim, Man-Jeong Paik, Jongkyeong Chung, Jin-Hong Kim, Chanhee Kang.
      Whereas cholesterol is vital for cell growth, proliferation, and remodeling, dysregulation of cholesterol metabolism is associated with multiple age-related pathologies. Here we show that senescent cells accumulate cholesterol in lysosomes to maintain the senescence-associated secretory phenotype (SASP). We find that induction of cellular senescence by diverse triggers enhances cellular cholesterol metabolism. Senescence is associated with the upregulation of the cholesterol exporter ABCA1, which is rerouted to the lysosome, where it moonlights as a cholesterol importer. Lysosomal cholesterol accumulation results in the formation of cholesterol-rich microdomains on the lysosomal limiting membrane enriched with the mammalian target of rapamycin complex 1 (mTORC1) scaffolding complex, thereby sustaining mTORC1 activity to support the SASP. We further show that pharmacological modulation of lysosomal cholesterol partitioning alters senescence-associated inflammation and in vivo senescence during osteoarthritis progression in male mice. Our study reveals a potential unifying theme for the role of cholesterol in the aging process through the regulation of senescence-associated inflammation.
    DOI:  https://doi.org/10.1038/s42255-023-00747-5
  19. Cell Death Dis. 2023 Feb 25. 14(2): 160
    Sestrin2: multifaceted functions, molecular basis, and its implications in liver diseases.
    Chunfeng Lu, Yiming Jiang, Wenxuan Xu, Xiaofeng Bao.
      Sestrin2 (SESN2), a highly conserved stress-responsive protein, can be triggered by various noxious stimuli, such as hypoxia, DNA damage, oxidative stress, endoplasmic reticulum (ER) stress, and inflammation. Multiple transcription factors regulate SESN2 expression, including hypoxia-inducible factor 1 (HIF-1), p53, nuclear factor E2-related factor 2 (Nrf2), activating transcription factor 4 (ATF4), ATF6, etc. Upon induction, SESN2 generally leads to activation of adenosine monophosphate-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). To maintain cellular homeostasis, SESN2 and its downstream molecules directly scavenge reactive oxygen species or indirectly influence the expression patterns of key genes associated with redox, macroautophagy, mitophagy, ER stress, apoptosis, protein synthesis, and inflammation. In liver diseases including acute liver injury, fatty liver diseases, hepatic fibrosis, and hepatocellular carcinoma (HCC), SESN2 is abnormally expressed and correlated with disease progression. In NAFLD, SESN2 helps with postponing disease progression through balancing glycolipid metabolism and macroautophagy (lipophagy), and rectifying oxidative damage and ER stress. During hepatic fibrosis, SESN2 represses HSCs activation and intrahepatic inflammation, hindering the occurrence and progress of fibrogenesis. However, the role of SESN2 in HCC is controversial due to its paradoxical pro-autophagic and anti-apoptotic effects. In conclusion, this review summarizes the biological functions of SESN2 in hypoxia, genotoxic stress, oxidative stress, ER stress, and inflammation, and specifically emphasizes the pathophysiological significance of SESN2 in liver diseases, aiming to providing a comprehensive understanding for SESN2 as a potential therapeutic target in liver diseases.
    DOI:  https://doi.org/10.1038/s41419-023-05669-4
  20. Autophagy. 2023 Mar 02. 1-15
    N protein of PEDV plays chess game with host proteins by selective autophagy.
    Xueying Zhai, Ning Kong, Yu Zhang, Yiyi Song, Wenzhen Qin, Xinyu Yang, Chenqian Ye, Manqing Ye, Wu Tong, Changlong Liu, Hao Zheng, Hai Yu, Wen Zhang, Xia Yang, Gaiping Zhang, Guangzhi Tong, Tongling Shan.
      Macroautophagy/autophagy is a cellular degradation and recycling process that maintains the homeostasis of organisms. The protein degradation role of autophagy has been widely used to control viral infection at multiple levels. In the ongoing evolutionary arms race, viruses have developed various ways to hijack and subvert autophagy in favor of its replication. It is still unclear exactly how autophagy affects or inhibits viruses. In this study, we have found a novel host restriction factor, HNRNPA1, that could inhibit PEDV replication by degrading viral nucleocapsid (N) protein. The restriction factor activates the HNRNPA1-MARCHF8/MARCH8-CALCOCO2/NDP52-autophagosome pathway with the help of transcription factor EGR1 targeting the HNRNPA1 promoter. HNRNPA1 could also promote the expression of IFN to facilitate the host antiviral defense response for antagonizing PEDV infection through RIGI protein interaction. During viral replication, we found that PEDV can, in contrast, degrade the host antiviral proteins HNRNPA1 and others (FUBP3, HNRNPK, PTBP1, and TARDBP) through its N protein through the autophagy pathway. These results reveal the dual function of selective autophagy in PEDV N and host proteins, which could promote the ubiquitination of viral particles and host antiviral proteins and degradation both of the proteins to regulate the relationship between virus infection and host innate immunity.Abbreviations: 3-MA: 3-methyladenine; ATG: autophagy related; Baf A1: bafilomycin A1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; ChIP: chromatin immunoprecipitation; Co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; GPI: glycosyl-phosphatidylinositol; hpi: hours post infection; MARCHF8/MARCH8: membrane-associated ring-CH-type finger 8; MOI: multiplicity of infection; N protein: nucleocapsid protein; PEDV: porcine epidemic diarrhea virus; siRNA: small interfering RNA; TCID50: 50% tissue culture infectious doses.
    Keywords:  HNRNPA1; IFN; PEDV; nucleocapsid protein; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2181615
  21. Autophagy. 2023 Feb 27.
    The inflammation repressor TNIP1/ABIN-1 is degraded by autophagy following TBK1 phosphorylation of its LIR.
    Nikoline Lander Rasmussen, Jianwen Zhou, Hallvard Olsvik, Stéphanie Kaeser-Pebernard, Trond Lamark, Joern Dengjel, Terje Johansen.
      The inflammatory repressor TNIP1/ABIN-1 is important for keeping in check inflammatory and cell-death pathways to avoid potentially dangerous sustained activation of these pathways. We have now found that TNIP1 is rapidly degraded by selective macroautophagy/autophagy early (0-4 h) after activation of TLR3 by poly(I:C)-treatment to allow expression of pro-inflammatory genes and proteins. A few hours later (6 h), TNIP1 levels rise again to counteract sustained inflammatory signalling. TBK1-mediated phosphorylation of a TNIP1 LIR motif regulates selective autophagy of TNIP1 by stimulating interaction with Atg8-family proteins. This is a novel level of regulation of TNIP1, whose protein level is crucial for controlling inflammatory signalling.
    Keywords:  ABIN-1; Atg8; LIR; TBK1; TNIP1; autophagy; inflammation
    DOI:  https://doi.org/10.1080/15548627.2023.2185013
  22. Nat Rev Gastroenterol Hepatol. 2023 Mar 01.
    Mucus secretion from colonic goblet cells is regulated by autophagy and ER stress.
    Jordan Hindson.
      
    DOI:  https://doi.org/10.1038/s41575-023-00761-8
  23. PLoS Biol. 2023 Feb;21(2): e3002002
    AlphaFold-multimer predicts ATG8 protein binding motifs crucial for autophagy research.
    Hallvard Lauritz Olsvik, Terje Johansen.
      In this issue of PLOS Biology, Ibrahim and colleagues demonstrate how AlphaFold-multimer, an artificial intelligence-based structure prediction tool, can be used to identify sequence motifs binding to the ATG8 family of proteins central to autophagy.
    DOI:  https://doi.org/10.1371/journal.pbio.3002002
  24. Biochem Biophys Res Commun. 2023 Feb 24. pii: S0006-291X(23)00249-8. [Epub ahead of print]653 76-82
    FPR1 is essential for rapamycin-induced lifespan extension in Saccharomyces cerevisiae.
    Gulperi Yalcin, Juri Kim, Dongseong Seo, Cheol-Koo Lee.
      FK506-sensitive proline rotamase 1 protein (Fpr1p), which is a homologue of the mammalian prolyl isomerase FK506-binding protein of 12 kDa (FKBP12), is known to play important roles in protein folding and prevention of protein aggregation. Although rapamycin is known to bind to Fpr1p to inhibit Tor1p mediated-mechanistic Target Of Rapamycin (mTOR) activity, the physiological functions of Fpr1p on lifespan remain unclear. In this study, we used the eukaryotic model Saccharomyces cerevisiae to demonstrate that deletion of FPR1 reduced yeast chronological lifespan (CLS), and there was no benefit on lifespan upon rapamycin treatment, indicating that lifespan extension mechanism of rapamycin in yeast is exclusively dependent on FPR1. Furthermore, there was a significant increase in CLS of fpr1Δ cells during caloric restriction (CR), suggesting that rapamycin affects lifespan in a different way compared to CR. This study highlights the importance of FPR1 for rapamycin-induced lifespan extension.
    Keywords:  Budding yeast; FPR1; Lifespan extension; Rapamycin; TOR1
    DOI:  https://doi.org/10.1016/j.bbrc.2023.02.063
  25. bioRxiv. 2023 Feb 24. pii: 2023.02.24.529955. [Epub ahead of print]
    Multi-modal Proteomic Characterization of Lysosomal Function and Proteostasis in Progranulin-Deficient Neurons.
    Saadia Hasan, Michael S Fernandopulle, Stewart W Humble, Ashley M Frankenfield, Haorong Li, Ryan Prestil, Kory R Johnson, Brent J Ryan, Richard Wade-Martins, Michael E Ward, Ling Hao.
      Progranulin (PGRN) is a lysosomal protein implicated in various neurodegenerative diseases. Over 70 mutations discovered in the GRN gene all result in reduced expression of PGRN protein. However, the detailed molecular function of PGRN within lysosomes and the impact of PGRN deficiency on lysosomal biology remain unclear. Here we leveraged multifaceted proteomic techniques to comprehensively characterize how PGRN deficiency changes the molecular and functional landscape of neuronal lysosomes. Using lysosome proximity labeling and immuno-purification of intact lysosomes, we characterized lysosome compositions and interactomes in both human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons (i 3 Neurons) and mouse brains. Using dynamic stable isotope labeling by amino acids in cell culture (dSILAC) proteomics, we measured global protein half-lives in i 3 Neurons for the first time and characterized the impact of progranulin deficiency on neuronal proteostasis. Together, this study indicated that PGRN loss impairs the lysosome’s degradative capacity with increased levels of v-ATPase subunits on the lysosome membrane, increased catabolic enzymes within the lysosome, elevated lysosomal pH, and pronounced alterations in neuron protein turnover. Collectively, these results suggested PGRN as a critical regulator of lysosomal pH and degradative capacity, which in turn influences global proteostasis in neurons. The multi-modal techniques developed here also provided useful data resources and tools to study the highly dynamic lysosome biology in neurons.
    DOI:  https://doi.org/10.1101/2023.02.24.529955
  26. J Assist Reprod Genet. 2023 Mar 04.
    BNIP3-mediated autophagy via the mTOR/ULK1 pathway induces primordial follicle loss after ovarian tissue transplantation.
    Fengxia Liu, Mujun Li.
      PURPOSE: To explore the underlying mechanism of primordial follicle loss in the early period following ovarian tissue transplantation (OTT).METHODS: BNIP3 was selected through bioinformatic protocols, as the hub gene related to autophagy during OTT. BNIP3 and autophagy in mice ovarian grafts and in hypoxia-mimicking KGN cells were detected using immunohistochemistry, transmission electron microscopy (TEM), western blotting, qPCR, and fluorescence staining. The regulatory role played by BNIP3 overexpression and the silencing of KGN cells in autophagy via the mTOR/ULK1 pathway was investigated.
    RESULTS: Ultrastructure examination showed that autophagic vacuoles increased after mice ovarian auto-transplantation. The BNIP3 and autophagy-related proteins (Beclin-1, LC3B, and SQSTM1/p62) in mice ovarian granulosa cells of primordial follicle from ovarian grafts were altered compared with the control. Administration of an autophagy inhibitor in mice decreased the depletion of primordial follicles. In vitro experiments indicated that BNIP3 and autophagy activity were upregulated in KGN cells treated with cobalt chloride (CoCl2). The overexpression of BNIP3 activated autophagy, whereas the silencing of BNIP3 suppressed it and reversed the autophagy induced by CoCl2 in KGN cells. Western blotting analysis showed the inhibition of mTOR and activation of ULK1 in KGN cells treated with CoCl2 and in the overexpression of BNIP3, and the opposite results following BNIP3 silencing. The activation of mTOR reversed the autophagy induced by BNIP3 overexpression.
    CONCLUSIONS: BNIP3-induced autophagy is crucial in primordial follicle loss during OTT procedure, and BNIP3 is a potential therapeutic target for primordial follicle loss after OTT.
    Keywords:  Autophagy; BNIP3; Ovarian tissue transplantation; mTOR/ULK1 pathway
    DOI:  https://doi.org/10.1007/s10815-023-02765-4
  27. Exp Neurol. 2023 Feb 26. pii: S0014-4886(23)00042-0. [Epub ahead of print]363 114358
    UBE3A deficiency-induced autophagy is associated with activation of AMPK-ULK1 and p53 pathways.
    Xiaoning Hao, Jiandong Sun, Li Zhong, Michel Baudry, Xiaoning Bi.
      Angelman Syndrome (AS) is a neurodevelopmental disorder caused by deficiency of the maternally expressed UBE3A gene. The UBE3A proteins functions both as an E3 ligase in the ubiquitin-proteasome system (UPS), and as a transcriptional co-activator for steroid hormone receptors. Here we investigated the effects of UBE3A deficiency on autophagy in the cerebellum of AS mice and in COS1 cells. Numbers and size of LC3- and LAMP2-immunopositive puncta were increased in cerebellar Purkinje cells of AS mice, as compared to wildtype mice. Western blot analysis showed an increase in the conversion of LC3I to LC3II in AS mice, as expected from increased autophagy. Levels of active AMPK and of one of its substrates, ULK1, a factor involved in autophagy initiation, were also increased. Colocalization of LC3 with LAMP2 was increased and p62 levels were decreased, indicating an increase in autophagy flux. UBE3A deficiency was also associated with reduced levels of phosphorylated p53 in the cytosol and increased levels in nuclei, which favors autophagy induction. UBE3A siRNA knockdown in COS-1 cells resulted in increased size and intensity of LC3-immunopositive puncta and increased the LC3 II/I ratio, as compared to control siRNA-treated cells, confirming the results found in the cerebellum of AS mice. These results indicate that UBE3A deficiency enhances autophagic activity through activation of the AMPK-ULK1 pathway and alterations in p53.
    Keywords:  Angelman syndrome; COS-1 cells; Cerebellum; LC3; Lysosome; TFEB; mTOR; p62; siRNA
    DOI:  https://doi.org/10.1016/j.expneurol.2023.114358
  28. Kaohsiung J Med Sci. 2023 Mar 03.
    Formosanin C suppresses cancer cell proliferation and migration by impeding autophagy machinery.
    Man-Ling Chu, Pei-Wen Lin, Yu-Wen Liu, Shan-Ying Wu, Sheng-Hui Lan, Chun-Li Su, Hsiao-Sheng Liu.
      Formosanin C (FC) is a natural compound extracted from Paris formosana Hayata with anticancer activity. FC induces both autophagy and apoptosis in human lung cancer cells. FC-induced depolarization of mitochondrial membrane potential (MMP) may trigger mitophagy. In this study, we clarified the effect of FC on autophagy, mitophagy, and the role of autophagy in FC-related cell death and motility. We found FC caused the continuous increase of LC3 II (representing autophagosomes) from 24 to 72 h without degradation after treatment of lung and colon cancer cells, indicating that FC blocks autophagic progression. In addition, we confirmed that FC also induces early stage autophagic activity. Altogether, FC is not only an inducer but also a blocker of autophagy progression. Moreover, FC increased MMP accompanied by overexpression of COX IV (mitochondria marker) and phosphorylated Parkin (p-Parkin, mitophagy marker) in lung cancer cells, but no colocalization of LC3 with COX IV or p-Parkin was detected under confocal microscopy. Moreover, FC could not block CCCP (mitophagy inducer)-induced mitophagy. These results imply that FC disrupts mitochondria dynamics in the treated cells, and the underlying mechanism deserves further exploration. Functional analysis reveals that FC suppresses cell proliferation and motility through apoptosis and EMT-related pathway, respectively. In conclusion, FC acts as an inducer as well as a blocker of autophagy that results in cancer cell apoptosis and decreased motility. Our findings shed the light on the development of combined therapy with FC and clinical anticancer drugs for cancer treatment.
    Keywords:  autophagy; formosanin C; lung cancer; mitophagy
    DOI:  https://doi.org/10.1002/kjm2.12658
  29. Toxicology. 2023 Feb 26. pii: S0300-483X(23)00054-9. [Epub ahead of print]487 153468
    Autophagy dysregulation in trichloroethene-mediated inflammation and autoimmune response.
    Hui Wang, Nivedita Banerjee, Gangduo Wang, M Firoze Khan.
      Trichloroethene (TCE), an organic solvent extensively used for degreasing metals, can cause inflammatory autoimmune disorders [i.e., systemic lupus erythematosus (SLE) and autoimmune hepatitis] from both environmental and occupational exposure. Autophagy has emerged as a pivotal pathogenic factor in various autoimmune diseases. However, role of autophagy dysregulation in TCE-mediated autoimmunity is largely unknown. Here, we investigate whether autophagy dysregulation contributes to pathogenesis of TCE-mediated autoimmune responses. Using our established mouse model, we observed TCE-treated mice had elevated MDA-protein adducts, microtubule-associated protein light chain 3 conversion (LC3-II/LC3-I), beclin-1, phosphorylation of AMP-activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) phosphorylation in the livers of MRL+ /+ mice. Suppression of oxidative stress with antioxidant N-acetylcysteine (NAC) effectively blocked TCE-mediated induction of autophagy markers. On the other hand, pharmacological autophagy induction with rapamycin significantly reduced TCE-mediated hepatic inflammation (NLRP3, ASC, Caspase1 and IL1-β mRNA levels), systemic cytokines (IL-12 and IL-17) and autoimmune responses (ANA and anti-dsDNA levels). Taken together, these results suggest that autophagy plays a protective role against TCE-mediated hepatic inflammation and autoimmunity in MRL+ /+ mice. These novel findings on the regulation of autophagy could help in designing therapeutic strategies for chemical exposure-mediated autoimmune responses.
    Keywords:  Autoimmunity; Autophagy; Inflammation; Oxidative stress; Trichloroethene
    DOI:  https://doi.org/10.1016/j.tox.2023.153468
  30. Front Oncol. 2023 ;13 1091118
    Autophagy-dependent ferroptosis as a potential treatment for glioblastoma.
    Yangchun Xie, Tao Hou, Jinyou Liu, Haixia Zhang, Xianling Liu, Rui Kang, Daolin Tang.
      Glioblastoma (GBM) is the most common malignant primary brain tumor with a poor 5-year survival rate. Autophagy is a conserved intracellular degradation system that plays a dual role in GBM pathogenesis and therapy. On one hand, stress can lead to unlimited autophagy to promote GBM cell death. On the other hand, elevated autophagy promotes the survival of glioblastoma stem cells against chemotherapy and radiation therapy. Ferroptosis is a type of lipid peroxidation-mediated regulated necrosis that initially differs from autophagy and other types of cell death in terms of cell morphology, biochemical characteristics, and the gene regulators involved. However, recent studies have challenged this view and demonstrated that the occurrence of ferroptosis is dependent on autophagy, and that many regulators of ferroptosis are involved in the control of autophagy machinery. Functionally, autophagy-dependent ferroptosis plays a unique role in tumorigenesis and therapeutic sensitivity. This mini-review will focus on the mechanisms and principles of autophagy-dependent ferroptosis and its emerging implications in GBM.
    Keywords:  autophagy; ferroptosis; glioblasoma; glioblastom stem cells; therapeutics
    DOI:  https://doi.org/10.3389/fonc.2023.1091118
  31. Curr Biol. 2023 Feb 22. pii: S0960-9822(23)00164-1. [Epub ahead of print]
    K63-linked ubiquitin chains are a global signal for endocytosis and contribute to selective autophagy in plants.
    Bushra Saeed, Florian Deligne, Carla Brillada, Kai Dünser, Franck Aniset Ditengou, Ilona Turek, Alaa Allahham, Nenad Grujic, Yasin Dagdas, Thomas Ott, Jürgen Kleine-Vehn, Grégory Vert, Marco Trujillo.
      In contrast to other eukaryotic model organisms, the closely related ubiquitin (Ub)-conjugating enzymes UBC35 and UBC36 are the main sources of K63-linked Ub chains in Arabidopsis.1 Although K63-linked chains have been associated with the regulation of vesicle trafficking, definitive proof for their role in endocytosis was missing. We show that the ubc35 ubc36 mutant has pleiotropic phenotypes related to hormone and immune signaling. Specifically, we reveal that ubc35-1 ubc36-1 plants have altered turnover of integral membrane proteins including FLS2, BRI1, and PIN1 at the plasma membrane. Our data indicates that K63-Ub chains are generally required for endocytic trafficking in plants. In addition, we show that in plants K63-Ub chains are involved in selective autophagy through NBR1, the second major pathway delivering cargoes to the vacuole for degradation. Similar to autophagy-defective mutants, ubc35-1 ubc36-1 plants display an accumulation of autophagy markers. Moreover, autophagy receptor NBR1 interacts with K63-Ub chains, which are required for its delivery to the lytic vacuole.2 Together, we show that K63-Ub chains act as a general signal required for the two main pathways delivering cargo to the vacuole and thus, to maintain proteostasis.
    Keywords:  E2; endocytosis; signaling; ubiquitin; ubiquitin-conjugating enzymes; vesicle trafficking
    DOI:  https://doi.org/10.1016/j.cub.2023.02.024
  32. Anticancer Drugs. 2023 Feb 24. pii: e001425. [Epub ahead of print]
    A novel combination of isovanillin, curcumin, and harmine (GZ17-6.02) enhances cell death and alters signaling in actinic keratoses cells when compared to individual components and two-component combinations.
    Zachary A Bordeaux, Shawn G Kwatra, Laurence Booth, Paul Dent.
      Actinic keratosis is a pre-malignant skin disease caused by excessive exposure to ultraviolet light. The present studies further defined the biology of a novel combination of isovanillin, curcumin, and harmine in actinic keratosis cells in vitro. An oral formulation (GZ17-6.02) and topical preparation (GZ21T) comprised of the same fixed, stoichiometric ratio have been developed. Together, the three active ingredients killed actinic keratosis cells more effectively than any of its component parts as either individual agents or when combined in pairs. The three active ingredients caused greater levels of DNA damage than any of its component parts as either individual agents or when combined in pairs. As a single agent, compared to isolated components, GZ17-6.02/GZ21T caused significantly greater activation of PKR-like endoplasmic reticulum kinase, the AMP-dependent protein kinase, and ULK1 and significantly reduced the activities of mTORC1, AKT, and YAP. Knockdown of the autophagy-regulatory proteins ULK1, Beclin1, or ATG5 significantly reduced the lethality of GZ17-6.02/GZ21T alone. Expression of an activated mammalian target of rapamycin mutant suppressed autophagosome formation and autophagic flux and reduced tumor cell killing. Blockade of both autophagy and death receptor signaling abolished drug-induced actinic keratosis cell death. Our data demonstrate that the unique combination of isovanillin, curcumin, and harmine represents a novel therapeutic with the potential to treat actinic keratosis in a manner different from the individual components or pairs of the components.
    DOI:  https://doi.org/10.1097/CAD.0000000000001425
  33. Oxid Med Cell Longev. 2023 ;2023 1649842
    Mitophagy and Traumatic Brain Injury: Regulatory Mechanisms and Therapeutic Potentials.
    Yi Luan, Lulu Jiang, Ying Luan, Yi Xie, Yang Yang, Kai-Di Ren.
      Traumatic brain injury (TBI), a kind of external trauma-induced brain function alteration, has posed a financial burden on the public health system. TBI pathogenesis involves a complicated set of events, including primary and secondary injuries that can cause mitochondrial damage. Mitophagy, a process in which defective mitochondria are specifically degraded, segregates and degrades defective mitochondria allowing a healthier mitochondrial network. Mitophagy ensures that mitochondria remain healthy during TBI, determining whether neurons live or die. Mitophagy acts as a critical regulator in maintaining neuronal survival and healthy. This review will discuss the TBI pathophysiology and the consequences of the damage it causes to mitochondria. This review article will explore the mitophagy process, its key factors, and pathways and reveal the role of mitophagy in TBI. Mitophagy will be further recognized as a therapeutic approach in TBI. This review will offer new insights into mitophagy's role in TBI progression.
    DOI:  https://doi.org/10.1155/2023/1649842
  34. Autophagy. 2023 Feb 28. 1-23
    HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies.
    Barbara Tedesco, Leen Vendredy, Elias Adriaenssens, Marta Cozzi, Bob Asselbergh, Valeria Crippa, Riccardo Cristofani, Paola Rusmini, Veronica Ferrari, Elena Casarotto, Marta Chierichetti, Francesco Mina, Paola Pramaggiore, Mariarita Galbiati, Margherita Piccolella, Jonathan Baets, Femke Baeke, Riet De Rycke, Vincent Mouly, Tommaso Laurenzi, Ivano Eberini, Anna Vihola, Bjarne Udd, Lan Weiss, Virginia Kimonis, Vincent Timmerman, Angelo Poletti.
      Chaperone-assisted selective autophagy (CASA) is a highly selective pathway for the disposal of misfolding and aggregating proteins. In muscle, CASA assures muscle integrity by favoring the turnover of structural components damaged by mechanical strain. In neurons, CASA promotes the removal of aggregating substrates. A crucial player of CASA is HSPB8 (heat shock protein family B (small) member 8), which acts in a complex with HSPA, their cochaperone BAG3, and the E3 ubiquitin ligase STUB1. Recently, four novel HSPB8 frameshift (fs) gene mutations have been linked to neuromyopathies, and encode carboxy-terminally mutated HSPB8, sharing a common C-terminal extension. Here, we analyzed the biochemical and functional alterations associated with the HSPB8_fs mutant proteins. We demonstrated that HSPB8_fs mutants are highly insoluble and tend to form proteinaceous aggregates in the cytoplasm. Notably, all HSPB8 frameshift mutants retain their ability to interact with CASA members but sequester them into the HSPB8-positive aggregates together with two autophagy receptors SQSTM1/p62 and TAX1BP1. This copartitioning process negatively affects the CASA capability to remove its clients and causes a general failure in proteostasis response. Further analyses revealed that the aggregation of the HSPB8_fs mutants occurs independently of the other CASA members or from the autophagy receptors interaction, but it is an intrinsic feature of the mutated amino acid sequence. HSPB8_fs mutants aggregation alters the differentiation capacity of muscle cells and impairs sarcomere organization. Collectively, these results shed light on a potential pathogenic mechanism shared by the HSPB8_fs mutants described in neuromuscular diseases.Abbreviations : ACD: α-crystallin domain; ACTN: actinin alpha; BAG3: BAG cochaperone 3; C: carboxy; CASA: chaperone-assisted selective autophagy; CE: carboxy-terminal extension; CLEM: correlative light and electron microscopy; CMT2L: Charcot-Marie-Tooth type 2L; CTR: carboxy-terminal region; dHMNII: distal hereditary motor neuropathy type II; EV: empty vector; FRA: filter retardation assay; fs: frameshift; HSPA/HSP70: heat shock protein family A (Hsp70); HSPB1/Hsp27: heat shock protein family B (small) member 1; HSPB8/Hsp22: heat shock protein family B (small) member 8; HTT: huntingtin; KO: knockout; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MD: molecular dynamics; MTOC: microtubule organizing center; MYH: myosin heavy chain; MYOG: myogenin; NBR1: NBR1 autophagy cargo receptor; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; NSC34: Neuroblastoma X Spinal Cord 34; OPTN: optineurin; polyQ: polyglutamine; SQSTM1/p62: sequestosome 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TARDBP/TDP-43: TAR DNA binding protein; TAX1BP1: Tax1 binding protein 1; TUBA: tubulin alpha; WT: wild-type.
    Keywords:  BAG3; CASA; HSPA; HSPB8; misfolding; myopathy; neuromuscular disorders; neuropathy; protein quality control
    DOI:  https://doi.org/10.1080/15548627.2023.2179780
  35. Cell Rep. 2023 Mar 02. pii: S2211-1247(23)00191-2. [Epub ahead of print]42(3): 112180
    Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson's disease GBA-N370S dopamine neurons.
    Helle Bogetofte, Brent J Ryan, Pia Jensen, Sissel I Schmidt, Dana L E Vergoossen, Mike B Barnkob, Lisa N Kiani, Uroosa Chughtai, Rachel Heon-Roberts, Maria Claudia Caiazza, William McGuinness, Ricardo Márquez-Gómez, Jane Vowles, Fiona S Bunn, Janine Brandes, Peter Kilfeather, Jack P Connor, Hugo J R Fernandes, Tara M Caffrey, Morten Meyer, Sally A Cowley, Martin R Larsen, Richard Wade-Martins.
      Variants at the GBA locus, encoding glucocerebrosidase, are the strongest common genetic risk factor for Parkinson's disease (PD). To understand GBA-related disease mechanisms, we use a multi-part-enrichment proteomics and post-translational modification (PTM) workflow, identifying large numbers of dysregulated proteins and PTMs in heterozygous GBA-N370S PD patient induced pluripotent stem cell (iPSC) dopamine neurons. Alterations in glycosylation status show disturbances in the autophagy-lysosomal pathway, which concur with upstream perturbations in mammalian target of rapamycin (mTOR) activation in GBA-PD neurons. Several native and modified proteins encoded by PD-associated genes are dysregulated in GBA-PD neurons. Integrated pathway analysis reveals impaired neuritogenesis in GBA-PD neurons and identify tau as a key pathway mediator. Functional assays confirm neurite outgrowth deficits and identify impaired mitochondrial movement in GBA-PD neurons. Furthermore, pharmacological rescue of glucocerebrosidase activity in GBA-PD neurons improves the neurite outgrowth deficit. Overall, this study demonstrates the potential of PTMomics to elucidate neurodegeneration-associated pathways and potential drug targets in complex disease models.
    Keywords:  CP: Neuroscience; Parkinson’s; glucocerebrosidase; glycosylation; iPSC; lysosome; neuritogenesis; phosphoproteomics; post-translational modifications; proteomics; stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2023.112180
  36. J Cachexia Sarcopenia Muscle. 2023 Mar 02.
    Molecular mechanisms of cancer cachexia-related loss of skeletal muscle mass: data analysis from preclinical and clinical studies.
    Agnès Martin, Yann S Gallot, Damien Freyssenet.
      Cancer cachexia is a systemic hypoanabolic and catabolic syndrome that diminishes the quality of life of cancer patients, decreases the efficiency of therapeutic strategies and ultimately contributes to decrease their lifespan. The depletion of skeletal muscle compartment, which represents the primary site of protein loss during cancer cachexia, is of very poor prognostic in cancer patients. In this review, we provide an extensive and comparative analysis of the molecular mechanisms involved in the regulation of skeletal muscle mass in human cachectic cancer patients and in animal models of cancer cachexia. We summarize data from preclinical and clinical studies investigating how the protein turnover is regulated in cachectic skeletal muscle and question to what extent the transcriptional and translational capacities, as well as the proteolytic capacity (ubiquitin-proteasome system, autophagy-lysosome system and calpains) of skeletal muscle are involved in the cachectic syndrome in human and animals. We also wonder how regulatory mechanisms such as insulin/IGF1-AKT-mTOR pathway, endoplasmic reticulum stress and unfolded protein response, oxidative stress, inflammation (cytokines and downstream IL1ß/TNFα-NF-κB and IL6-JAK-STAT3 pathways), TGF-ß signalling pathways (myostatin/activin A-SMAD2/3 and BMP-SMAD1/5/8 pathways), as well as glucocorticoid signalling, modulate skeletal muscle proteostasis in cachectic cancer patients and animals. Finally, a brief description of the effects of various therapeutic strategies in preclinical models is also provided. Differences in the molecular and biochemical responses of skeletal muscle to cancer cachexia between human and animals (protein turnover rates, regulation of ubiquitin-proteasome system and myostatin/activin A-SMAD2/3 signalling pathways) are highlighted and discussed. Identifying the various and intertwined mechanisms that are deregulated during cancer cachexia and understanding why they are decontrolled will provide therapeutic targets for the treatment of skeletal muscle wasting in cancer patients.
    Keywords:  Autophagy-lysosome; Cancer cachexia; Glucocorticoids; Inflammation; Myostatin; Oxidative stress; Proteostasis; Skeletal muscle; Ubiquitin-proteasome
    DOI:  https://doi.org/10.1002/jcsm.13073
  37. Adv Biol (Weinh). 2023 Mar 03. e2200221
    Systematic Transmission Electron Microscopy-Based Identification and 3D Reconstruction of Cellular Degradation Machinery.
    Kit Neikirk, Zer Vue, Prasanna Katti, Ben I Rodriguez, Salem Omer, Jianqiang Shao, Trace Christensen, Edgar Garza Lopez, Andrea Marshall, Caroline B Palavicino-Maggio, Jessica Ponce, Ahmad F Alghanem, Larry Vang, Taylor Barongan, Heather K Beasley, Taylor Rodman, Dominique Stephens, Margaret Mungai, Marcelo Correia, Vernat Exil, Steven Damo, Sandra A Murray, Amber Crabtree, Brian Glancy, Renata O Pereira, E Dale Abel, Antentor O Hinton.
      Various intracellular degradation organelles, including autophagosomes, lysosomes, and endosomes, work in tandem to perform autophagy, which is crucial for cellular homeostasis. Altered autophagy contributes to the pathophysiology of various diseases, including cancers and metabolic diseases. This paper aims to describe an approach to reproducibly identify and distinguish subcellular structures involved in macroautophagy. Methods are provided that help avoid common pitfalls. How to distinguish between lysosomes, lipid droplets, autolysosomes, autophagosomes, and inclusion bodies are also discussed. These methods use transmission electron microscopy (TEM), which is able to generate nanometer-scale micrographs of cellular degradation components in a fixed sample. Serial block face-scanning electron microscopy is also used to visualize the 3D morphology of degradation machinery using the Amira software. In addition to TEM and 3D reconstruction, other imaging techniques are discussed, such as immunofluorescence and immunogold labeling, which can be used to classify cellular organelles, reliably and accurately. Results show how these methods may be used to accurately quantify cellular degradation machinery under various conditions, such as treatment with the endoplasmic reticulum stressor thapsigargin or ablation of the dynamin-related protein 1.
    Keywords:  3D reconstruction; autophagosomes; autophagy; lysosomes; transmission electron microscopy
    DOI:  https://doi.org/10.1002/adbi.202200221
  38. Heliyon. 2023 Feb;9(2): e13691
    Euphejolkinolide A, a new ent-abietane lactone from Euphorbia peplus L. with promising biological activity in activating the autophagy-lysosomal pathway.
    Xiaoqian Ran, Qing-Yun Lu, Ying-Yao Li, Xue-Xue Pu, Yarong Guo, Ming-Rui Yuan, Shi-Peng Guan, Mao Sun, Lijin Jiao, Yong-Gang Yao, Ying-Tong Di, Xiao-Jiang Hao, Rongcan Luo.
      A new ent-abietane diterpenoid, named Euphejolkinolide A (1), was isolated from the whole plant of Euphorbia peplus L. Its structure, including absolute configurations, was determined by spectroscopic analyses and was corroborated by single-crystal X-ray diffraction analysis. This new compound was assessed for its activity to induce lysosome biogenesis through Lyso-Tracker Red staining, in which compound 1 could significantly induce lysosome biogenesis. In addition, quantitative real-time PCR (qRT-PCR) analysis demonstrated a direct correlation between the observed lysosome biogenesis and the transcriptional activation of the lysosomal genes after treatment with the compound 1. Moreover, compound 1 promoted autophagic flux by upregulating LC3-II and downregulating SQSTM1 in both human microglia cells and U251 cells, which is required for cellular homeostasis. Further results suggested 1 induced lysosome biogenesis and autophagy which was mediated by TFEB (transcription factor EB). The structure activity relationships (SAR) analysis suggested that the carbony1 at C-7 in 1 might be a key active group. Overall, the current data suggested that 1 could be a potential compound for lysosome disorder therapy by induction of autophagy.
    Keywords:  Autophagy-lysosomal pathway; Ent-abietane diterpenoid; Euphejolkinolide A; Euphorbia peplus L.; Euphorbiaceae
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e13691
  39. Chem Biol Drug Des. 2023 Mar 03.
    Biological functions and structural biology of Plasmodium falciparum autophagy-related proteins: the under-explored options for novel antimalarial drug design.
    Mohammed Aliyu Usman, Abdulmalik Abdullahi Salman, Mohammed Auwal Ibrahim, Koji Furukawa, Kazuhiko Yamasaki.
      Malaria remains a threat to global public health and the available antimalarial drugs are undermined by side effects and parasite resistance, suggesting an emphasis on new potential targets. Amongst the novel targets, Plasmodium falciparum autophagy-related proteins (PfAtg) remain a priority. In this paper, we reviewed the existing knowledge on the functions and structural biology of PfAtg including the compounds with inhibitory activity toward P. falciparum Atg8-Atg3 protein-protein interaction (PfAtg8-PfAtg3 PPI). A total of five PfAtg (PfAtg5, PfAtg8, PfAtg12, PfAtg18, and Rab7) were observed to have autophagic and/or non-autophagic roles. Moreover, available data showed that PfAtg8 has conserved hydrophobic pockets, which allows it to interact with PfAtg3 to form PfAtg8-PfAtg3 PPI. Additionally, 2-bromo-N-(4-pyridin-2-yl-1,3-thiazol-2-yl) benzamide was identified as the most powerful inhibitor of PfAtg8-PfAtg3 PPI. Due to the dearth of knowledge in this field, we hope that the article would open an avenue to further research on the remaining PfAtg as possible drug candidates.
    Keywords:  Plasmodium falciparum; autophagy; autophagy-related proteins; protein-protein interaction; protein-protein interaction inhibitors
    DOI:  https://doi.org/10.1111/cbdd.14225
  40. iScience. 2023 Mar 17. 26(3): 106105
    ACKR4a induces autophagy to block NF-κB signaling and apoptosis to facilitate Vibrio harveyi infection.
    Ya Chen, Baolan Cao, Weiwei Zheng, Tianjun Xu.
      Autophagy and apoptosis are two recognized mechanisms of resistance to bacterial invasion. However, bacteria have likewise evolved the ability to evade immunity. In this study, we identify ACKR4a, a member of an atypical chemokine receptor family, as a suppressor of the NF-κB pathway, which cooperates with Beclin-1 to induce autophagy to inhibit NF-κB signaling and block apoptosis, facilitating Vibrio harveyi infection. Mechanistically, V. harveyi-induced Ap-1 activates ACKR4a transcription and expression. ACKR4a forms a complex with Beclin-1 and MyD88, respectively, inducing autophagy and transporting MyD88 into the lysosome for degradation to suppress inflammatory cytokine production. Meanwhile, ACKR4a-induced autophagy blocks apoptosis by inhibiting caspase8. This study proves for the first time that V. harveyi uses both autophagy and apoptosis to evade innate immunity, suggesting that V. harveyi has evolved the ability to against fish immunity.
    Keywords:  Bacteriology; Components of the immune system; Immune response
    DOI:  https://doi.org/10.1016/j.isci.2023.106105
  41. STAR Protoc. 2023 Jan 23. pii: S2666-1667(22)00751-1. [Epub ahead of print]4(1): 101871
    Quantification of autophagy flux in isolated mouse skeletal muscle fibers with overexpression of fluorescent protein mCherry-EGFP-LC3.
    Xinyu Zhou, Ju Hwan Cho, Jianxun Yi, Kyounghan Choi, Ki Ho Park, Hua Zhu, Chuanxi Cai, Erin Haggard, Jingsong Zhou, Jae-Kyun Ko, Jianjie Ma.
      Evaluation of autophagy flux could be challenging for muscle fibers due to the baseline expression of mCherry-EGFP-LC3 along the Z-line. We established a protocol to overcome this difficulty. We overexpress mChery-EGFP-LC3 in the FDB muscle of an adult mouse via electroporation. Then, we enzymatically digest FDB muscle to yield individual fibers for live cell imaging. Finally, we develop an ImageJ-based program to eliminate the baseline striation pattern and semi-automatically quantify autophagosomes (APs) and autolysosomes (ALs) for autophagy flux analysis.
    Keywords:  Cell Biology; Microscopy; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2022.101871
  42. Am J Physiol Gastrointest Liver Physiol. 2023 Feb 28.
    Intestinal epithelial autophagy is required for the regenerative benefit of calorie restriction.
    Patrick A Williams, Kaitlyn E Naughton, Lauren A Simon, Gloria E Soto, Louis R Parham, Xianghui Ma, Charles H Danan, Weiming Hu, Elliot S Friedman, Emily A McMillan, Hritik Mehta, Madison A Stoltz, Joshua Soto Ocaña, Joseph Zackular, Kyle Bittinger, Kelly A Whelan, Tatiana A Karakasheva, Kathryn E Hamilton.
      Calorie restriction can enhance the regenerative capacity of the injured intestinal epithelium. Among other metabolic changes, calorie restriction can activate the autophagy pathway. While independent studies have attributed the regenerative benefit of calorie restriction to downregulation of mTORC1, it is not known whether autophagy itself is required for the regenerative benefit of calorie restriction. We used mouse and organoid models with autophagy gene deletion to evaluate the contribution of autophagy to intestinal epithelial regeneration following calorie restriction. In the absence of injury, mice with intestinal epithelial-specific deletion of autophagy gene Atg7 (Atg7ΔIEC) exhibit weight loss and histological changes similar to wildtype mice following calorie restriction. Conversely, calorie restricted Atg7ΔIEC mice displayed a significant reduction in regenerative crypt foci following irradiation compared to calorie restricted wildtype mice. Targeted analyses of tissue metabolites in calorie restricted mice revealed an association between calorie restriction and reduced glycocholic acid (GCA) in wildtype but not Atg7ΔIEC mice. To evaluate whether GCA can directly modulate epithelial stem cell self-renewal, we performed enteroid formation assays with or without GCA. Wildtype enteroids exhibited reduced enteroid formation efficiency in response to GCA treatment, suggesting that reduced availability of GCA during calorie restriction may be one mechanism by which calorie restriction favors epithelial regeneration in a manner dependent upon epithelial autophagy. Taken together, our data support the premise that intestinal epithelial Atg7 is required for the regenerative benefit of calorie restriction, due in part to its role in modulating luminal GCA with direct effects on epithelial stem cell self-renewal.
    Keywords:  Autophagy; Calorie Restriction; GCA; Intestinal Epithelium; Regeneration
    DOI:  https://doi.org/10.1152/ajpgi.00248.2022
  43. FEBS J. 2023 Mar 03.
    MAEL facilitates metabolic reprogramming and breast cancer progression by promoting the degradation of citrate synthase and fumarate hydratase via chaperone-mediated autophagy.
    Lin Zhou, Shuobo Ou, Ting Liang, Meiling Li, Pei Xiao, Jiaxin Cheng, Jianlin Zhou, Liqin Yuan.
      Metabolic reprogramming is a hallmark of cancer. Several studies have shown that inactivation of Krebs cycle enzymes, such as citrate synthase (CS) and fumarate hydratase (FH), facilitates aerobic glycolysis and cancer progression. MAEL has been shown to play an oncogenic role in bladder, liver, colon and gastric cancers, but its role in breast cancer and metabolism is still unknown. Here, we demonstrated that MAEL promoted malignant behaviors and aerobic glycolysis in breast cancer cells. Mechanistically, MAEL interacted with CS/FH and HSAP8 via its MAEL domain and HMG domain, respectively, and then enhanced the binding affinity of CS/FH with HSPA8, facilitating the transport of CS/FH to the lysosome for degradation. MAEL-induced degradation of CS and FH could be suppressed by the lysosome inhibitors leupeptin and NH4 Cl, but not by the macroautophagy inhibitor 3-MA or the proteasome inhibitor MG132. These results suggested that MAEL promoted the degradation of CS and FH via chaperone-mediated autophagy (CMA). Further studies showed that the expression of MAEL was significantly and negatively correlated with CS and FH in breast cancer. Moreover, overexpression of CS or/and FH could reverse the oncogenic effects of MAEL. Taken together, MAEL promotes a metabolic shift from oxidative phosphorylation to glycolysis by inducing CMA-dependent degradation of CS and FH, thereby promoting breast cancer progression. These findings have elucidated a novel molecular mechanism of MAEL in cancer.
    Keywords:  MAEL; breast cancer; chaperone-mediated autophagy; citrate synthase; fumarate hydratase; metabolic reprogramming
    DOI:  https://doi.org/10.1111/febs.16768
  44. Biochem Biophys Res Commun. 2023 Feb 16. pii: S0006-291X(23)00209-7. [Epub ahead of print]652 121-130
    l-Asparaginase regulates mTORC1 activity via a TSC2-dependent pathway in pancreatic beta cells.
    Masako Seike, Shun-Ichiro Asahara, Hiroyuki Inoue, Michiyo Kudo, Ayumi Kanno, Aisha Yokoi, Hirotaka Suzuki, Maki Kimura-Koyanagi, Yoshiaki Kido, Wataru Ogawa.
      Eif2ak4, a susceptibility gene for type 2 diabetes, encodes GCN2, a molecule activated by amino acid deficiency. Mutations or deletions in GCN2 in pancreatic β-cells increase mTORC1 activity by decreasing Sestrin2 expression in a TSC2-independent manner. In this study, we searched for molecules downstream of GCN2 that suppress mTORC1 activity in a TSC2-dependent manner. To do so, we used a pull-down assay to identify molecules that competitively inhibit the binding of the T1462 phosphorylation site of TSC2 to 14-3-3. l-asparaginase was identified. Although l-asparaginase is frequently used as an anticancer drug for acute lymphoblastic leukemia, little is known about endogenous l-asparaginase. l-Asparaginase, which is expressed downstream of GCN2, was found to bind 14-3-3 and thereby to inhibit its binding to the T1462 phosphorylation site of TSC2 and contribute to TSC2 activation and mTORC1 inactivation upon TSC2 dephosphorylation. Further investigation of the regulation of mTORC1 activity in pancreatic β-cells by l-asparaginase should help to elucidate the mechanism of diabetes and insulin secretion failure during anticancer drug use.
    Keywords:  14-3-3; GCN2; Pancreatic β-cell; TSC2; l-Asparaginase; mTORC1 activity
    DOI:  https://doi.org/10.1016/j.bbrc.2023.02.035
  45. PLoS Biol. 2023 Mar;21(3): e3001977
    An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets.
    Natalia Moskal, Naomi P Visanji, Olena Gorbenko, Vijay Narasimhan, Hannah Tyrrell, Jess Nash, Peter N Lewis, G Angus McQuibban.
      Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin, but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets (LDs) and mitochondria. Conversely, LD expansion, which occurs following mitochondrial damage, was suppressed by probucol and probucol-mediated mitophagy enhancement required LDs. Probucol-mediated LD dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage.
    DOI:  https://doi.org/10.1371/journal.pbio.3001977
  46. Ann Med Surg (Lond). 2023 Feb;85(2): 323-325
    Autophagy and Alzheimer's disease: How far science has to be progressed? - correspondence.
    Talha B Emran, Hitesh Chopra, Kuldeep Dhama.
      
    DOI:  https://doi.org/10.1097/MS9.0000000000000156
  47. Mol Neurobiol. 2023 Feb 28.
    Mitochondrial Hydrogen Peroxide Activates PTEN and Inactivates Akt Leading to Autophagy Inhibition-Dependent Cell Death in Neuronal Models of Parkinson's Disease.
    Qianyun Yu, Ruijie Zhang, Tianjing Li, Liu Yang, Zhihan Zhou, Long Hou, Wen Wu, Rui Zhao, Xiaoling Chen, Yajie Yao, Shile Huang, Long Chen.
      Defective autophagy relates to the pathogenesis of Parkinson's disease (PD), a typical neurodegenerative disease. Our recent study has demonstrated that PD toxins (6-OHDA, MPP+, or rotenone) induce neuronal apoptosis by impeding the AMPK/Akt-mTOR signaling. Here, we show that treatment with 6-OHDA, MPP+, or rotenone triggered decreases of ATG5/LC3-II and autophagosome formation with a concomitant increase of p62 in PC12, SH-SY5Y cells, and primary neurons, suggesting inhibition of autophagy. Interestingly, overexpression of wild-type ATG5 attenuated the inhibitory effect of PD toxins on autophagy, reducing neuronal apoptosis. The effects of PD toxins on autophagy and apoptosis were found to be associated with activation of PTEN and inactivation of Akt. Overexpression of dominant negative PTEN, constitutively active Akt and/or pretreatment with rapamycin rescued the cells from PD toxins-induced downregulation of ATG5/LC3-II and upregulation of p62, as well as consequential autophagosome diminishment and apoptosis in the cells. The effects of PD toxins on autophagy and apoptosis linked to excessive intracellular and mitochondrial hydrogen peroxide (H2O2) production, as evidenced by using a H2O2-scavenging enzyme catalase, a mitochondrial superoxide indicator MitoSOX and a mitochondria-selective superoxide scavenger Mito-TEMPO. Furthermore, we observed that treatment with PD toxins reduced the protein level of Parkin in the cells. Knockdown of Parkin alleviated the effects of PD toxins on H2O2 production, PTEN/Akt activity, autophagy, and apoptosis in the cells, whereas overexpression of wild-type Parkin exacerbated these effects of PD toxins, implying the involvement of Parkin in the PD toxins-induced oxidative stress. Taken together, the results indicate that PD toxins can elicit mitochondrial H2O2, which can activate PTEN and inactivate Akt leading to autophagy inhibition-dependent neuronal apoptosis, and Parkin plays a critical role in this process. Our findings suggest that co-manipulation of the PTEN/Akt/autophagy signaling by antioxidants may be exploited for the prevention of neuronal loss in PD.
    Keywords:  Akt; Autophagy; H2O2; Neuronal cells; PTEN; Parkin
    DOI:  https://doi.org/10.1007/s12035-023-03286-y
  48. Nat Commun. 2023 Mar 03. 14(1): 1214
    mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion.
    Heng-Jia Liu, Heng Du, Damir Khabibullin, Mahsa Zarei, Kevin Wei, Gordon J Freeman, David J Kwiatkowski, Elizabeth P Henske.
      Identifying the mechanisms underlying the regulation of immune checkpoint molecules and the therapeutic impact of targeting them in cancer is critical. Here we show that high expression of the immune checkpoint B7-H3 (CD276) and high mTORC1 activity correlate with immunosuppressive phenotypes and worse clinical outcomes in 11,060 TCGA human tumors. We find that mTORC1 upregulates B7-H3 expression via direct phosphorylation of the transcription factor YY2 by p70 S6 kinase. Inhibition of B7-H3 suppresses mTORC1-hyperactive tumor growth via an immune-mediated mechanism involving increased T-cell activity and IFN-γ responses coupled with increased tumor cell expression of MHC-II. CITE-seq reveals strikingly increased cytotoxic CD38+CD39+CD4+ T cells in B7-H3-deficient tumors. In pan-human cancers, a high cytotoxic CD38+CD39+CD4+ T-cell gene signature correlates with better clinical prognosis. These results show that mTORC1-hyperactivity, present in many human tumors including tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), drives B7-H3 expression leading to suppression of cytotoxic CD4+ T cells.
    DOI:  https://doi.org/10.1038/s41467-023-36881-7
  49. EMBO Rep. 2023 Feb 27. e54731
    Saturated fatty acids increase LPI to reduce FUNDC1 dimerization and stability and mitochondrial function.
    Linbo Chen, Qianping Zhang, Yuanyuan Meng, Tian Zhao, Chenglong Mu, Changying Fu, Caijuan Deng, Jianyu Feng, Siling Du, Wei Liu, Guangfeng Geng, Kaili Ma, Hongcheng Cheng, Qiangqiang Liu, Qian Luo, Jiaojiao Zhang, Zhanqiang Du, Lin Cao, Hui Wang, Yong Liu, Jianping Lin, Guo Chen, Lei Liu, Sin Man Lam, Guanghou Shui, Yushan Zhu, Quan Chen.
      Ectopic lipid deposition and mitochondrial dysfunction are common etiologies of obesity and metabolic disorders. Excessive dietary uptake of saturated fatty acids (SFAs) causes mitochondrial dysfunction and metabolic disorders, while unsaturated fatty acids (UFAs) counterbalance these detrimental effects. It remains elusive how SFAs and UFAs differentially signal toward mitochondria for mitochondrial performance. We report here that saturated dietary fatty acids such as palmitic acid (PA), but not unsaturated oleic acid (OA), increase lysophosphatidylinositol (LPI) production to impact on the stability of the mitophagy receptor FUNDC1 and on mitochondrial quality. Mechanistically, PA shifts FUNDC1 from dimer to monomer via enhanced production of LPI. Monomeric FUNDC1 shows increased acetylation at K104 due to dissociation of HDAC3 and increased interaction with Tip60. Acetylated FUNDC1 can be further ubiquitinated by MARCH5 for proteasomal degradation. Conversely, OA antagonizes PA-induced accumulation of LPI, and FUNDC1 monomerization and degradation. A fructose-, palmitate-, and cholesterol-enriched (FPC) diet also affects FUNDC1 dimerization and promotes its degradation in a non-alcoholic steatohepatitis (NASH) mouse model. We thus uncover a signaling pathway that orchestrates lipid metabolism with mitochondrial quality.
    Keywords:  FUNDC1; fatty acid metabolism; membrane protein dimerization; mitochondrial quality control
    DOI:  https://doi.org/10.15252/embr.202254731
  50. J Cell Sci. 2023 Mar 01. pii: jcs260662. [Epub ahead of print]136(5):
    StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival.
    Felicity R Sterling, Jon D'Amico, Alexandria M Brumfield, Kara L Huegel, Patricia S Vaughan, Kathryn Morris, Shelby Schwarz, Michelle V Joyce, Bill Boggess, Matthew M Champion, Kevin Maciuba, Philip Allen, Eric Marasco, Grant Koch, Peter Gonzalez, Shannon Hodges, Shannon Leahy, Erica Gerstbauer, Edward H Hinchcliffe, Kevin T Vaughan.
      The pathological accumulation of cholesterol is a signature feature of Niemann-Pick type C (NPC) disease, in which excessive lipid levels induce Purkinje cell death in the cerebellum. NPC1 encodes a lysosomal cholesterol-binding protein, and mutations in NPC1 drive cholesterol accumulation in late endosomes and lysosomes (LE/Ls). However, the fundamental role of NPC proteins in LE/L cholesterol transport remains unclear. Here, we demonstrate that NPC1 mutations impair the projection of cholesterol-containing membrane tubules from the surface of LE/Ls. A proteomic survey of purified LE/Ls identified StARD9 as a novel lysosomal kinesin responsible for LE/L tubulation. StARD9 contains an N-terminal kinesin domain, a C-terminal StART domain, and a dileucine signal shared with other lysosome-associated membrane proteins. Depletion of StARD9 disrupts LE/L tubulation, paralyzes bidirectional LE/L motility and induces accumulation of cholesterol in LE/Ls. Finally, a novel StARD9 knock-out mouse recapitulates the progressive loss of Purkinje cells in the cerebellum. Together, these studies identify StARD9 as a microtubule motor protein responsible for LE/L tubulation and provide support for a novel model of LE/L cholesterol transport that becomes impaired in NPC disease.
    Keywords:  Cholesterol; Kinesin; Lysosome; Membrane tubulation; Niemann–Pick type C disease
    DOI:  https://doi.org/10.1242/jcs.260662
  51. Autophagy. 2023 Feb 26. 1-20
    Endolysosomal impairment by binding of amyloid beta or MAPT/Tau to V-ATPase and rescue via the HYAL-CD44 axis in Alzheimer disease.
    Seo-Hyun Kim, Young-Sin Cho, Youbin Kim, Jisu Park, Seung-Min Yoo, Jimin Gwak, Youngwon Kim, Youngdae Gwon, Tae-In Kam, Yong-Keun Jung.
      Impaired activities and abnormally enlarged structures of endolysosomes are frequently observed in Alzheimer disease (AD) brains. However, little is known about whether and how endolysosomal dysregulation is triggered and associated with AD. Here, we show that vacuolar ATPase (V-ATPase) is a hub that mediates proteopathy of oligomeric amyloid beta (Aβ) and hyperphosphorylated MAPT/Tau (p-MAPT/Tau). Endolysosomal integrity was largely destroyed in Aβ-overloaded or p-MAPT/Tau-positive neurons in culture and AD brains, which was a necessary step for triggering neurotoxicity, and treatments with acidic nanoparticles or endocytosis inhibitors rescued the endolysosomal impairment and neurotoxicity. Interestingly, we found that the lumenal ATP6V0C and cytosolic ATP6V1B2 subunits of the V-ATPase complex bound to the internalized Aβ and cytosolic PHF-1-reactive MAPT/Tau, respectively. Their interactions disrupted V-ATPase activity and accompanying endolysosomal activity in vitro and induced neurodegeneration. Using a genome-wide functional screen, we isolated a suppressor, HYAL (hyaluronidase), which reversed the endolysosomal dysfunction and proteopathy and alleviated the memory impairment in 3xTg-AD mice. Further, we found that its metabolite hyaluronic acid (HA) and HA receptor CD44 attenuated neurotoxicity in affected neurons via V-ATPase. We propose that endolysosomal V-ATPase is a bona fide proteotoxic receptor that binds to pathogenic proteins and deteriorates endolysosomal function in AD, leading to neurodegeneration in proteopathy.Abbreviations: AAV, adeno-associated virus; Aβ, amyloid beta; AD, Alzheimer disease; APP, amyloid beta precursor protein; ATP6V0C, ATPase H+ transporting V0 subunit c; ATP6V1A, ATPase H+ transporting V1 subunit A; ATP6V1B2, ATPase H+ transporting V1 subunit B2; CD44.Fc, CD44-mouse immunoglobulin Fc fusion construct; Co-IP, co-immunoprecipitation; CTSD, cathepsin D; HA, hyaluronic acid; HMWHA, high-molecular-weight hyaluronic acid; HYAL, hyaluronidase; i.c.v, intracerebroventricular; LMWHA, low-molecular-weight hyaluronic acid; NPs, nanoparticles; p-MAPT/Tau, hyperphosphorylated microtubule associated protein tau; PI3K, phosphoinositide 3-kinase; V-ATPase, vacuolar-type H+-translocating ATPase; WT, wild-type.
    Keywords:  Alzheimer disease; MAPT/Tau; V-ATPase; amyloid beta; endolysosome; hyaluronidase-CD44; proteopathy
    DOI:  https://doi.org/10.1080/15548627.2023.2181614
  52. Nat Commun. 2023 Feb 28. 14(1): 947
    Cell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis.
    David Paul, Omer Stern, Yvonne Vallis, Jatinder Dhillon, Andrew Buchanan, Harvey McMahon.
      The ability of cells to manage consequences of exogenous proteotoxicity is key to cellular homeostasis. While a plethora of well-characterised machinery aids intracellular proteostasis, mechanisms involved in the response to denaturation of extracellular proteins remain elusive. Here we show that aggregation of protein ectodomains triggers their endocytosis via a macroendocytic route, and subsequent lysosomal degradation. Using ERBB2/HER2-specific antibodies we reveal that their cross-linking ability triggers specific and fast endocytosis of the receptor, independent of clathrin and dynamin. Upon aggregation, canonical clathrin-dependent cargoes are redirected into the aggregation-dependent endocytosis (ADE) pathway. ADE is an actin-driven process, which morphologically resembles macropinocytosis. Physical and chemical stress-induced aggregation of surface proteins also triggers ADE, facilitating their degradation in the lysosome. This study pinpoints aggregation of extracellular domains as a trigger for rapid uptake and lysosomal clearance which besides its proteostatic function has potential implications for the uptake of pathological protein aggregates and antibody-based therapies.
    DOI:  https://doi.org/10.1038/s41467-023-36496-y
  53. J Clin Neurol. 2023 Mar;19(2): 101-114
    Proteostasis and Ribostasis Impairment as Common Cell Death Mechanisms in Neurodegenerative Diseases.
    Su Min Lim, Minyeop Nahm, Seung Hyun Kim.
      The cellular homeostasis of proteins (proteostasis) and RNA metabolism (ribostasis) are essential for maintaining both the structure and function of the brain. However, aging, cellular stress conditions, and genetic contributions cause disturbances in proteostasis and ribostasis that lead to protein misfolding, insoluble aggregate deposition, and abnormal ribonucleoprotein granule dynamics. In addition to neurons being primarily postmitotic, nondividing cells, they are more susceptible to the persistent accumulation of abnormal aggregates. Indeed, defects associated with the failure to maintain proteostasis and ribostasis are common pathogenic components of age-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, the neuronal deposition of misfolded and aggregated proteins can cause both increased toxicity and impaired physiological function, which lead to neuronal dysfunction and cell death. There is recent evidence that irreversible liquid-liquid phase separation (LLPS) is responsible for the pathogenic aggregate formation of disease-related proteins, including tau, α-synuclein, and RNA-binding proteins, including transactive response DNA-binding protein 43, fused in sarcoma, and heterogeneous nuclear ribonucleoprotein A1. Investigations of LLPS and its control therefore suggest that chaperone/disaggregase, which reverse protein aggregation, are valuable therapeutic targets for effective treatments for neurological diseases. Here we review and discuss recent studies to highlight the importance of understanding the common cell death mechanisms of proteostasis and ribostasis in neurodegenerative diseases.
    Keywords:  cell death mechanism; liquid–liquid phase separation; neurodegenerative disease; proteostasis; ribostasis
    DOI:  https://doi.org/10.3988/jcn.2022.0379
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