bims-apauto 2022-07-10 papers

Issue of 2022–07–10
six papers selected by
Su Hyun Lee, Seoul National University

Mol Cell. 2022 Jun 28. pii: S1097-2765(22)00577-9. [Epub ahead of print]

Ubiquitin profiling of lysophagy identifies actin stabilizer CNN2 as a target of VCP/p97 and uncovers a link to HSPB1.

Bojana Kravić, Tihana Bionda, Alexander Siebert, Pinki Gahlot, Sophie Levantovsky, Christian Behrends, Hemmo Meyer.

Lysosomal membrane permeabilization (LMP) is an underlying feature of diverse conditions including neurodegeneration. Cells respond by extensive ubiquitylation of membrane-associated proteins for clearance of the organelle through lysophagy that is facilitated by the ubiquitin-directed AAA-ATPase VCP/p97. Here, we assessed the ubiquitylated proteome upon acute LMP and uncovered a large diversity of targets and lysophagy regulators. They include calponin-2 (CNN2) that, along with the Arp2/3 complex, translocates to damaged lysosomes and regulates actin filaments to drive phagophore formation. Importantly, CNN2 needs to be ubiquitylated during the process and removed by VCP/p97 for efficient lysophagy. Moreover, we identified the small heat shock protein HSPB1 that assists VCP/p97 in the extraction of CNN2 and show that other membrane regulators including SNAREs, PICALM, AGFG1, and ARL8B are ubiquitylated during lysophagy. Our data reveal a framework of how ubiquitylation and two effectors, VCP/p97 and HSPB1, cooperate to protect cells from the deleterious effects of LMP.

Keywords: AAA+ protein; HSPB1; VCP/p97; actin; autophagy; calponin; lysophagy; lysosome; ubiquitin

DOI: https://doi.org/10.1016/j.molcel.2022.06.012

Autophagy. 2022 Jul 04.

Secretory autophagy during lysosome inhibition (SALI).

Jayanta Debnath, Andrew M Leidal.

Both macroautophagy/autophagy and extracellular vesicle (EV) secretion pathways converge upon the endolysosome system. Although lysosome impairment leads to defects in autophagic degradation, the impact of such dysfunction on EV secretion remains poorly understood. Recently, we uncovered a novel secretory autophagy pathway that employs EVs and nanoparticles (EVPs) for the secretion of autophagy cargo receptors outside the cell when either autophagosome maturation or lysosomal function is blocked. We term this process secretory autophagy during lysosome inhibition (SALI). SALI functionally requires multiple steps in classical autophagosome formation and the small GTPase RAB27A. Because the intracellular accumulation of autophagy cargo receptors perturbs cell signaling and quality control pathways, we propose that SALI functions as a failsafe mechanism to preserve protein and cellular homeostasis when autophagic or lysosomal degradation is impaired.

Keywords: Autophagy cargo receptors; extracellular vesicles; lysosome; proteostasis; secretory autophagy; vesicular trafficking

DOI: https://doi.org/10.1080/15548627.2022.2095788

Autophagy. 2022 Jul 07. 1-4

SQSTM1, lipid droplets and current state of their lipophagy affairs.

Ankit Shroff, Taras Y Nazarko.

SQSTM1/p62 (sequestosome 1) is a well-established indicator of macroautophagic/autophagic flux. It was initially characterized as the ubiquitin-binding autophagic receptor in aggrephagy, the selective autophagy of ubiquitinated protein aggregates. Recently, several studies correlated its levels with the abundance of intracellular lipid droplets (LDs). In the absence of a bona fide receptor for the selective autophagy of LDs (lipophagy), a few studies demonstrated the role of SQSTM1 in lipophagy. Our analysis of these studies shows that SQSTM1 colocalizes with LDs, bridges them with phagophores, is co-degraded with them in the lysosomes, and affects LD abundance in a variety of cells and under diverse experimental conditions. Although only one study reported all these functions together, the overwhelming and complementary evidence from other studies suggests that the role of SQSTM1 in lipophagy via tagging, movement, aggregation/clustering and sequestration of LDs is rather a common phenomenon in mammalian cells. As ubiquitination of the LD-associated proteins under stress conditions is increasingly recognized as another common phenomenon, some other ubiquitin-binding autophagic receptors, such as NBR1 and OPTN, might soon join SQSTM1 on a list of the non-exclusive lipophagy receptors.Abbreviations: LD: lipid droplet; LIR: LC3-interacting region; PAT: Perilipin, ADRP and TIP47 domain; SAR: selective autophagy receptor.

Keywords: Lipid droplet; SAR; SQSTM1; lipophagy; lipophagy receptor; p62; phagophore; selective autophagy; selective autophagy receptor; ubiquitin

DOI: https://doi.org/10.1080/15548627.2022.2094606

Autophagy. 2022 Jul 04.

Mitochondrial Quality Control Links Two Seemingly Unrelated Neurodegenerative Diseases.

Yinglu Tang, Yunpeng Huang, Zhihui Wan, Bing Zhou, Zhihao Wu.

Keywords: Acetylation; CoA; Parkinson disease; Pink1/PINK1; autophagy receptor; fbl/PANK2; mitophagy; pantothenate kinase-associated neurodegeneration; park/PRKN

DOI: https://doi.org/10.1080/15548627.2022.2094605

Nat Commun. 2022 Jul 02. 13(1): 3812

Endosomal LC3C-pathway selectively targets plasma membrane cargo for autophagic degradation.

Paula P Coelho, Geoffrey G Hesketh, Annika Pedersen, Elena Kuzmin, Anne-Marie N Fortier, Emily S Bell, Colin D H Ratcliffe, Anne-Claude Gingras, Morag Park.

Autophagy selectively targets cargo for degradation, yet mechanistic understanding remains incomplete. The ATG8-family plays key roles in autophagic cargo recruitment. Here by mapping the proximal interactome of ATG8-paralogs, LC3B and LC3C, we uncover a LC3C-Endocytic-Associated-Pathway (LEAP) that selectively recruits plasma-membrane (PM) cargo to autophagosomes. We show that LC3C localizes to peripheral endosomes and engages proteins that traffic between PM, endosomes and autophagosomes, including the SNARE-VAMP3 and ATG9, a transmembrane protein essential for autophagy. We establish that endocytic LC3C binds cargo internalized from the PM, including the Met receptor tyrosine kinase and transferrin receptor, and is necessary for their recruitment into ATG9 vesicles targeted to sites of autophagosome initiation. Structure-function analysis identified that LC3C-endocytic localization and engagement with PM-cargo requires the extended carboxy-tail unique to LC3C, the TBK1 kinase, and TBK1-phosphosites on LC3C. These findings identify LEAP as an unexpected LC3C-dependent pathway, providing new understanding of selective coupling of PM signalling with autophagic degradation.

DOI: https://doi.org/10.1038/s41467-022-31465-3

Cell Death Dis. 2022 Jul 07. 13(7): 587

sGRP78 enhances selective autophagy of monomeric TLR4 to regulate myeloid cell death.

Zhenghao Wu, Zhuoshuo Xu, Xiaoqi Zhou, Heli Li, Liang Zhao, Yibing Lv, Yanyan Guo, Guanxin Shen, Yong He, Ping Lei.

Soluble glucose regulated protein 78 (sGRP78) has long been suggested as a mediator resolution of inflammation. We previously reported that sGRP78 induced the rapid endocytosis of TLR4 with defective TLR4 signaling. To elucidate the underlying mechanisms, in this study, we investigated how sGRP78 influenced the behavior and trafficking of TLR4 in myeloid cells. It was found that sGRP78 promoted LPS endocytosis with monomeric TLR4. This internalized monomeric TLR4 formed complexes with p62-LC3, and was degraded in autolysosomes. Furthermore, the sGRP78-enhanced autophagy-dependent TLR4 degradation caused apoptosis and ferroptosis in myeloid cells, contributing to the sGRP78-mediated resolution of inflammation. These reports establish innovative mechanisms for endotoxin clearance and immune regulation by TLR4 degradation, linking innate immunity with multiple ancient processes, including autophagy, apoptosis, and ferroptosis, together through a shared resolution-associated molecular pattern (RAMP)-sGRP78.

DOI: https://doi.org/10.1038/s41419-022-05048-5