bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2023‒05‒28
seven papers selected by
Su Hyun Lee
Harvard University
  1. Ubiquitination regulates ER-phagy and remodelling of endoplasmic reticulum.
  2. Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy.
  3. The role of autophagy in regulating metabolism in the tumor microenvironment.
  4. Metamorphic proteins at the basis of human autophagy initiation and lipid transfer.
  5. Autophagy regulates sex steroid hormone synthesis through lysosomal degradation of lipid droplets in human ovary and testis.
  6. Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
  7. A ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells.
  1. Nature. 2023 May 24.
    Ubiquitination regulates ER-phagy and remodelling of endoplasmic reticulum.
    Alexis González, Adriana Covarrubias-Pinto, Ramachandra M Bhaskara, Marius Glogger, Santosh K Kuncha, Audrey Xavier, Eric Seemann, Mohit Misra, Marina E Hoffmann, Bastian Bräuning, Ashwin Balakrishnan, Britta Qualmann, Volker Dötsch, Brenda A Schulman, Michael M Kessels, Christian A Hübner, Mike Heilemann, Gerhard Hummer, Ivan Dikić.
      The endoplasmic reticulum (ER) undergoes continuous remodelling via a selective autophagy pathway, known as ER-phagy1. ER-phagy receptors have a central role in this process2, but the regulatory mechanism remains largely unknown. Here we report that ubiquitination of the ER-phagy receptor FAM134B within its reticulon homology domain (RHD) promotes receptor clustering and binding to lipidated LC3B, thereby stimulating ER-phagy. Molecular dynamics (MD) simulations showed how ubiquitination perturbs the RHD structure in model bilayers and enhances membrane curvature induction. Ubiquitin molecules on RHDs mediate interactions between neighbouring RHDs to form dense receptor clusters that facilitate the large-scale remodelling of lipid bilayers. Membrane remodelling was reconstituted in vitro with liposomes and ubiquitinated FAM134B. Using super-resolution microscopy, we discovered FAM134B nanoclusters and microclusters in cells. Quantitative image analysis revealed a ubiquitin-mediated increase in FAM134B oligomerization and cluster size. We found that the E3 ligase AMFR, within multimeric ER-phagy receptor clusters, catalyses FAM134B ubiquitination and regulates the dynamic flux of ER-phagy. Our results show that ubiquitination enhances RHD functions via receptor clustering, facilitates ER-phagy and controls ER remodelling in response to cellular demands.
    DOI:  https://doi.org/10.1038/s41586-023-06089-2
  2. Nature. 2023 May 24.
    Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy.
    Hector Foronda, Yangxue Fu, Adriana Covarrubias-Pinto, Hartmut T Bocker, Alexis González, Eric Seemann, Patricia Franzka, Andrea Bock, Ramachandra M Bhaskara, Lutz Liebmann, Marina E Hoffmann, Istvan Katona, Nicole Koch, Joachim Weis, Ingo Kurth, Joseph G Gleeson, Fulvio Reggiori, Gerhard Hummer, Michael M Kessels, Britta Qualmann, Muriel Mari, Ivan Dikić, Christian A Hübner.
      Membrane-shaping proteins characterized by reticulon homology domains play an important part in the dynamic remodelling of the endoplasmic reticulum (ER). An example of such a protein is FAM134B, which can bind LC3 proteins and mediate the degradation of ER sheets through selective autophagy (ER-phagy)1. Mutations in FAM134B result in a neurodegenerative disorder in humans that mainly affects sensory and autonomic neurons2. Here we report that ARL6IP1, another ER-shaping protein that contains a reticulon homology domain and is associated with sensory loss3, interacts with FAM134B and participates in the formation of heteromeric multi-protein clusters required for ER-phagy. Moreover, ubiquitination of ARL6IP1 promotes this process. Accordingly, disruption of Arl6ip1 in mice causes an expansion of ER sheets in sensory neurons that degenerate over time. Primary cells obtained from Arl6ip1-deficient mice or from patients display incomplete budding of ER membranes and severe impairment of ER-phagy flux. Therefore, we propose that the clustering of ubiquitinated ER-shaping proteins facilitates the dynamic remodelling of the ER during ER-phagy and is important for neuronal maintenance.
    DOI:  https://doi.org/10.1038/s41586-023-06090-9
  3. Genes Dis. 2023 Mar;10(2): 447-456
    The role of autophagy in regulating metabolism in the tumor microenvironment.
    Panpan Zhang, Shanshan Cheng, Xiaonan Sheng, Huijuan Dai, Kang He, Yueyao Du.
      Autophagy, as a special programmed cell death, is a critical degradative process that eliminates intracellular abnormal proteins or damage organelles to balance cell energy and favor cell metabolism with autophagy-related (ATG) proteins. Autophagy activation is being increasingly recognized as an essential hallmark in tumorigenesis through influencing the metabolism of stromal cells in the tumor microenvironment (TME) which comprises of tumor cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs), immune cells and adipocytes. Tumor cells can reuse autophagy-involved recycling to maintain mitochondrial function and energy supply to meet the metabolic demand of their growth and proliferation. However, the mechanism through which autophagy can promote a crosstalk between tumor and stroma cells is not clear. Reprogramed metabolism is one of the main characteristics of TME leading to higher adaptability of tumor cells with diverse mechanisms. The activation of autophagy has expanded our understanding on the interaction between tumor metabolism and TME. The aim of this review is to report recent advances on the metabolic cross-talk between stromal cells and solid tumor cells induced by autophagy in TME and revealed potential therapeutic targets.
    Keywords:  Autophagy; Metabolism; Therapeutic targets; Tumor; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.gendis.2021.10.010
  4. Mol Cell. 2023 May 12. pii: S1097-2765(23)00321-0. [Epub ahead of print]
    Metamorphic proteins at the basis of human autophagy initiation and lipid transfer.
    Anh Nguyen, Francesca Lugarini, Céline David, Pouya Hosnani, Çağla Alagöz, Annabelle Friedrich, David Schlütermann, Barbora Knotkova, Anoshi Patel, Iwan Parfentev, Henning Urlaub, Michael Meinecke, Björn Stork, Alex C Faesen.
      Autophagy is a conserved intracellular degradation pathway that generates de novo double-membrane autophagosomes to target a wide range of material for lysosomal degradation. In multicellular organisms, autophagy initiation requires the timely assembly of a contact site between the ER and the nascent autophagosome. Here, we report the in vitro reconstitution of a full-length seven-subunit human autophagy initiation supercomplex built on a core complex of ATG13-101 and ATG9. Assembly of this core complex requires the rare ability of ATG13 and ATG101 to switch between distinct folds. The slow spontaneous metamorphic conversion is rate limiting for the self-assembly of the supercomplex. The interaction of the core complex with ATG2-WIPI4 enhances tethering of membrane vesicles and accelerates lipid transfer of ATG2 by both ATG9 and ATG13-101. Our work uncovers the molecular basis of the contact site and its assembly mechanisms imposed by the metamorphosis of ATG13-101 to regulate autophagosome biogenesis in space and time.
    Keywords:  autophagy; autophagy initiation; lipid transfer; membrane-contact site; metabolism; protein metamorphosis
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.026
  5. Cell Death Dis. 2023 May 26. 14(5): 342
    Autophagy regulates sex steroid hormone synthesis through lysosomal degradation of lipid droplets in human ovary and testis.
    Yashar Esmaeilian, Francesko Hela, Gamze Bildik, Ece İltumur, Sevgi Yusufoglu, Ceren Sultan Yildiz, Kayhan Yakin, Yakup Kordan, Ozgur Oktem.
      Autophagy is an evolutionarily conserved process that aims to maintain the energy homeostasis of the cell by recycling long-lived proteins and organelles. Previous studies documented the role of autophagy in sex steroid hormone biosynthesis in different animal models and human testis. Here we demonstrate in this study that sex steroid hormones estrogen and progesterone are produced through the same autophagy-mediated mechanism in the human ovary in addition to the human testis. In brief, pharmacological inhibition and genetic interruption of autophagy through silencing of autophagy genes (Beclin1 and ATG5) via siRNA and shRNA technologies significantly reduced basal and gonadotropin-stimulated estradiol (E2), progesterone (P4) and testosterone (T) production in the ex vivo explant tissue culture of ovary and testis and primary and immortalized granulosa cells. Consistent with the findings of the previous works, we observed that lipophagy, a special form of autophagy, mediates the association of the lipid droplets (LD)s with lysosome to deliver the lipid cargo within the LDs to lysosomes for degradation in order to release free cholesterol required for steroid synthesis. Gonadotropin hormones are likely to augment the production of sex steroid hormones by upregulating the expression of autophagy genes, accelerating autophagic flux and promoting the association of LDs with autophagosome and lysosome. Moreover, we detected some aberrations at different steps of lipophagy-mediated P4 production in the luteinized GCs of women with defective ovarian luteal function. The progression of autophagy and the fusion of the LDs with lysosome are markedly defective, along with reduced P4 production in these patients. Our data, together with the findings of the previous works, may have significant clinical implications by opening a new avenue in understanding and treatment of a wide range of diseases, from reproductive disorders to sex steroid-producing neoplasms, sex steroid-dependent malignancies (breast, endometrium, prostate) and benign disorders (endometriosis).
    DOI:  https://doi.org/10.1038/s41419-023-05864-3
  6. Nat Commun. 2023 May 24. 14(1): 2847
    Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
    Zoë P Van Acker, Anika Perdok, Ruben Hellemans, Katherine North, Inge Vorsters, Cedric Cappel, Jonas Dehairs, Johannes V Swinnen, Ragna Sannerud, Marine Bretou, Markus Damme, Wim Annaert.
      Phospholipase D3 (PLD3) polymorphisms are linked to late-onset Alzheimer's disease (LOAD). Being a lysosomal 5'-3' exonuclease, its neuronal substrates remained unknown as well as how a defective lysosomal nucleotide catabolism connects to AD-proteinopathy. We identified mitochondrial DNA (mtDNA) as a major physiological substrate and show its manifest build-up in lysosomes of PLD3-defective cells. mtDNA accretion creates a degradative (proteolytic) bottleneck that presents at the ultrastructural level as a marked abundance of multilamellar bodies, often containing mitochondrial remnants, which correlates with increased PINK1-dependent mitophagy. Lysosomal leakage of mtDNA to the cytosol activates cGAS-STING signaling that upregulates autophagy and induces amyloid precursor C-terminal fragment (APP-CTF) and cholesterol accumulation. STING inhibition largely normalizes APP-CTF levels, whereas an APP knockout in PLD3-deficient backgrounds lowers STING activation and normalizes cholesterol biosynthesis. Collectively, we demonstrate molecular cross-talks through feedforward loops between lysosomal nucleotide turnover, cGAS-STING and APP metabolism that, when dysregulated, result in neuronal endolysosomal demise as observed in LOAD.
    DOI:  https://doi.org/10.1038/s41467-023-38501-w
  7. Nat Commun. 2023 May 24. 14(1): 3002
    A ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells.
    Xue Li, Quan Jiang, Guiyu Song, Mahsa Nouri Barkestani, Qianxun Wang, Shaoxun Wang, Matthew Fan, Caodi Fang, Bo Jiang, Justin Johnson, Arnar Geirsson, George Tellides, Jordan S Pober, Dan Jane-Wit.
      Internalization of complement membrane attack complexes (MACs) assembles NLRP3 inflammasomes in endothelial cells (EC) and promotes IL-β-mediated tissue inflammation. Informed by proteomics analyses of FACS-sorted inflammasomes, we identify a protein complex modulating inflammasome activity on endosomes. ZFVYE21, a Rab5 effector, partners with Rubicon and RNF34, forming a "ZRR" complex that is stabilized in a Rab5- and ZFYVE21-dependent manner on early endosomes. There, Rubicon competitively disrupts inhibitory associations between caspase-1 and its pseudosubstrate, Flightless I (FliI), while RNF34 ubiquitinylates and degradatively removes FliI from the signaling endosome. The concerted actions of the ZRR complex increase pools of endosome-associated caspase-1 available for activation. The ZRR complex is assembled in human tissues, its associated signaling responses occur in three mouse models in vivo, and the ZRR complex promotes inflammation in a skin model of chronic rejection. The ZRR signaling complex reflects a potential therapeutic target for attenuating inflammasome-mediated tissue injury.
    DOI:  https://doi.org/10.1038/s41467-023-38684-2
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