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A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival

ABSTRACT: Lysosomal damage is a major threat to cell survival. Our previous work has reported that lysosomal damage induces stress granule (SG) formation. However, the significance of SG formation on cell fate and the precise mechanisms by which lysosomal damage triggers SG formation remains unclear. Here, we show that SG formation is initiated through a novel calcium-dependent pathway and plays a significant role in promoting cell survival in response to lysosomal damage. Mechanistically, we demonstrate that during lysosomal damage, ALIX (ALG2-interacting protein X) together with its partner, the calcium-binding protein ALG2, transduces lysosomal damage signals by detecting calcium leakage to induce SG formation by controlling the phosphorylation of eIF2alpah. ALIX facilities SG formation by coordinating the upstream regulation of eIF2alpha phosphorylation via PKR and PACT. We also found this regulatory event of SG formation occur on damaged lysosomes. Collectively, these investigations reveal novel insight into the precise regulation of SG formation, and the interaction between damaged lysosomes and stress granules. Importantly, SG formation is significant for promoting cell survival in the physiological context of lysosomal damage inflicted by SARS-CoV-2 ORF3a, adenovirus infection, Malaria hemozoin, proteopathic tau as well as environmental hazard silica.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Jingyue Jia

PROVIDER: MSV000093768 | MassIVE | Thu Jan 04 13:41:00 GMT 2024

SECONDARY ACCESSION(S): PXD048258

REPOSITORIES: MassIVE

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Project description:Removal of damaged organelles via the process of selective autophagy constitutes a major form of cellular quality control. Damaged organelles are recognized by a dedicated surveillance machinery, leading to the assembly of an autophagosome around the damaged organelle, prior to fusion with the degradative lysosomal compartment. Lysosomes themselves are also prone to damage and are degraded through the process of lysophagy. While early steps involve recognition of ruptured lysosomal membranes by glycan-binding Galectins and ubiquitylation of transmembrane lysosomal proteins, many steps in the process, and their inter-relationships, remain poorly understood, including the role and identity of cargo receptors required for completion of lysophagy. Here, we employ quantitative organelle capture and proximity biotinylation proteomics of autophagy adaptors, cargo receptors, and Galectins in response to acute lysosomal damage, thereby revealing the landscape of lysosomal proteome remodeling during lysophagy. Among proteins dynamically recruited to damaged lysosomes were ubiquitin-binding autophagic cargo receptors. Using newly developed lysophagic flux reporters including Lyso-Keima, we demonstrate that TAX1BP1, together with its associated kinase TBK1, are both necessary and sufficient to promote lysophagic flux in both Hela cells and induced neurons (iNeurons). While the related receptor OPTN can drive damage-dependent lysophagy when overexpressed, cells lacking either OPTN or CALCOCO2 still maintain significant lysophagic flux in HeLa cells. Mechanistically, TAX1BP1-driven lysophagy requires its N-terminal SKICH domain, which binds both TBK1 and the autophagy regulatory factor RB1CC1, and requires upstream ubiquitylation events for efficient recruitment and lysophagic flux. These results identify TAX1BP1 as a central component in the lysophagy pathway and provide a proteomic resource for future studies of the lysophagy process.

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A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival

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