bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2023–05–21
six papers selected by
Su Hyun Lee, Harvard University
  1. Integrated proteomics identifies p62-dependent selective autophagy of the supramolecular vault complex.
  2. SQSTM1/P62 promotes lysophagy via formation of liquid-like condensates maintained by HSP27.
  3. Unconventional initiation of PINK1/Parkin mitophagy by Optineurin.
  4. The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy.
  5. The role of the proteasome in mitochondrial protein quality control.
  6. Ubiquitin-independent proteasomal degradation driven by C-degron pathways.
  1. Dev Cell. 2023 May 09. pii: S1534-5807(23)00191-0. [Epub ahead of print]
    Integrated proteomics identifies p62-dependent selective autophagy of the supramolecular vault complex.
    Reo Kurusu, Yuki Fujimoto, Hideaki Morishita, Daisuke Noshiro, Shuhei Takada, Koji Yamano, Hideaki Tanaka, Ritsuko Arai, Shun Kageyama, Tomoko Funakoshi, Satoko Komatsu-Hirota, Hikari Taka, Saiko Kazuno, Yoshiki Miura, Masato Koike, Toshifumi Wakai, Satoshi Waguri, Nobuo N Noda, Masaaki Komatsu.
      In addition to membranous organelles, autophagy selectively degrades biomolecular condensates, in particular p62/SQSTM1 bodies, to prevent diseases including cancer. Evidence is growing regarding the mechanisms by which autophagy degrades p62 bodies, but little is known about their constituents. Here, we established a fluorescence-activated-particle-sorting-based purification method for p62 bodies using human cell lines and determined their constituents by mass spectrometry. Combined with mass spectrometry of selective-autophagy-defective mouse tissues, we identified vault, a large supramolecular complex, as a cargo within p62 bodies. Mechanistically, major vault protein directly interacts with NBR1, a p62-interacting protein, to recruit vault into p62 bodies for efficient degradation. This process, named vault-phagy, regulates homeostatic vault levels in vivo, and its impairment may be associated with non-alcoholic-steatohepatitis-derived hepatocellular carcinoma. Our study provides an approach to identifying phase-separation-mediated selective autophagy cargoes, expanding our understanding of the role of phase separation in proteostasis.
    Keywords:  Mallory-Denk body; NBR1; fluorescence-activated particle sorting; hepatocellular carcinoma; liquid-liquid phase separation; non-alcoholic steatohepatitis; p62/SQSTM1; selective autophagy; vault; vault-phagy
    DOI:  https://doi.org/10.1016/j.devcel.2023.04.015
  2. Autophagy. 2023 May 16. 1-2
    SQSTM1/P62 promotes lysophagy via formation of liquid-like condensates maintained by HSP27.
    Elizabeth R Gallagher, Erika L F Holzbaur.
       ABBREVIATIONS: SQSTM1/p62: Sequestosome-1; HSP27: Heat shock protein 27; LLPS: liquid-liquid phase separation; iPSC: induced pluripotent stem cell; PB1: Phox and Bem1p; FRAP: fluorescence recovery after photo-bleaching; ATG: autophagy-related; ALS: amyotrophic lateral sclerosis.
    Keywords:  HSP27; Lysosomes; Sqstm1/P62; lysophagy; neurodegeneration; phase separation
    DOI:  https://doi.org/10.1080/15548627.2023.2210943
  3. Mol Cell. 2023 May 18. pii: S1097-2765(23)00292-7. [Epub ahead of print]83(10): 1693-1709.e9
    Unconventional initiation of PINK1/Parkin mitophagy by Optineurin.
    Thanh Ngoc Nguyen, Justyna Sawa-Makarska, Grace Khuu, Wai Kit Lam, Elias Adriaenssens, Dorotea Fracchiolla, Stephen Shoebridge, Daniel Bernklau, Benjamin Scott Padman, Marvin Skulsuppaisarn, Runa S J Lindblom, Sascha Martens, Michael Lazarou.
      Cargo sequestration is a fundamental step of selective autophagy in which cells generate a double-membrane structure termed an "autophagosome" on the surface of cargoes. NDP52, TAX1BP1, and p62 bind FIP200, which recruits the ULK1/2 complex to initiate autophagosome formation on cargoes. How OPTN initiates autophagosome formation during selective autophagy remains unknown despite its importance in neurodegeneration. Here, we uncover an unconventional path of PINK1/Parkin mitophagy initiation by OPTN that does not begin with FIP200 binding or require the ULK1/2 kinases. Using gene-edited cell lines and in vitro reconstitutions, we show that OPTN utilizes the kinase TBK1, which binds directly to the class III phosphatidylinositol 3-kinase complex I to initiate mitophagy. During NDP52 mitophagy initiation, TBK1 is functionally redundant with ULK1/2, classifying TBK1's role as a selective autophagy-initiating kinase. Overall, this work reveals that OPTN mitophagy initiation is mechanistically distinct and highlights the mechanistic plasticity of selective autophagy pathways.
    Keywords:  OPTN; PINK1; Parkin; TBK1; autophagosome; autophagy; selective autophagy
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.021
  4. Mol Cell. 2023 May 06. pii: S1097-2765(23)00316-7. [Epub ahead of print]
    The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy.
    Tomoyuki Fukuda, Kentaro Furukawa, Tatsuro Maruyama, Shun-Ichi Yamashita, Daisuke Noshiro, Chihong Song, Yuta Ogasawara, Kentaro Okuyama, Jahangir Md Alam, Manabu Hayatsu, Tetsu Saigusa, Keiichi Inoue, Kazuho Ikeda, Akira Takai, Lin Chen, Vikramjit Lahiri, Yasushi Okada, Shinsuke Shibata, Kazuyoshi Murata, Daniel J Klionsky, Nobuo N Noda, Tomotake Kanki.
      Mitophagy plays an important role in mitochondrial homeostasis by selective degradation of mitochondria. During mitophagy, mitochondria should be fragmented to allow engulfment within autophagosomes, whose capacity is exceeded by the typical mitochondria mass. However, the known mitochondrial fission factors, dynamin-related proteins Dnm1 in yeasts and DNM1L/Drp1 in mammals, are dispensable for mitophagy. Here, we identify Atg44 as a mitochondrial fission factor that is essential for mitophagy in yeasts, and we therefore term Atg44 and its orthologous proteins mitofissin. In mitofissin-deficient cells, a part of the mitochondria is recognized by the mitophagy machinery as cargo but cannot be enwrapped by the autophagosome precursor, the phagophore, due to a lack of mitochondrial fission. Furthermore, we show that mitofissin directly binds to lipid membranes and brings about lipid membrane fragility to facilitate membrane fission. Taken together, we propose that mitofissin acts directly on lipid membranes to drive mitochondrial fission required for mitophagy.
    Keywords:  Atg44; autophagy; crystal structure analysis; dynamin-related protein; high-speed atomic force microscopy; mitochondria; mitochondrial fission; mitofissin; mitophagy; yeast
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.022
  5. IUBMB Life. 2023 May 13.
    The role of the proteasome in mitochondrial protein quality control.
    Saskia Rödl, Johannes M Herrmann.
      The abundance of each cellular protein is dynamically adjusted to the prevailing metabolic and stress conditions by modulation of their synthesis and degradation rates. The proteasome represents the major machinery for the degradation of proteins in eukaryotic cells. How the ubiquitin-proteasome system (UPS) controls protein levels and removes superfluous and damaged proteins from the cytosol and the nucleus is well characterized. However, recent studies showed that the proteasome also plays a crucial role in mitochondrial protein quality control. This mitochondria-associated degradation (MAD) thereby acts on two layers: first, the proteasome removes mature, functionally compromised or mis-localized proteins from the mitochondrial surface; and second, the proteasome cleanses the mitochondrial import pore of import intermediates of nascent proteins that are stalled during translocation. In this review, we provide an overview about the components and their specific functions that facilitate proteasomal degradation of mitochondrial proteins in the yeast Saccharomyces cerevisiae. Thereby we explain how the proteasome, in conjunction with a set of intramitochondrial proteases, maintains mitochondrial protein homeostasis and dynamically adapts the levels of mitochondrial proteins to specific conditions.
    Keywords:  mitochondria; mitochondria-associated degradation; proteasome; protein degradation; protein import; ubiquitin
    DOI:  https://doi.org/10.1002/iub.2734
  6. Mol Cell. 2023 May 09. pii: S1097-2765(23)00317-9. [Epub ahead of print]
    Ubiquitin-independent proteasomal degradation driven by C-degron pathways.
    Yaara Makaros, Anat Raiff, Richard T Timms, Ajay R Wagh, Mor Israel Gueta, Aizat Bekturova, Julia Guez-Haddad, Sagie Brodsky, Yarden Opatowsky, Michael H Glickman, Stephen J Elledge, Itay Koren.
      Although most eukaryotic proteins are targeted for proteasomal degradation by ubiquitination, a subset have been demonstrated to undergo ubiquitin-independent proteasomal degradation (UbInPD). However, little is known about the molecular mechanisms driving UbInPD and the degrons involved. Utilizing the GPS-peptidome approach, a systematic method for degron discovery, we found thousands of sequences that promote UbInPD; thus, UbInPD is more prevalent than currently appreciated. Furthermore, mutagenesis experiments revealed specific C-terminal degrons required for UbInPD. Stability profiling of a genome-wide collection of human open reading frames identified 69 full-length proteins subject to UbInPD. These included REC8 and CDCA4, proteins which control proliferation and survival, as well as mislocalized secretory proteins, suggesting that UbInPD performs both regulatory and protein quality control functions. In the context of full-length proteins, C termini also play a role in promoting UbInPD. Finally, we found that Ubiquilin family proteins mediate the proteasomal targeting of a subset of UbInPD substrates.
    Keywords:  C-degron; Global Protein Stability (GPS) technology; Ubiquilin; Ubiquitin; degron; proteasome; ubiquitin-independent degradation
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.023
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