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.
[doi:10.25345/C57S7J383]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: lysosomal damage
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Jingyue Jia, Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, USA |
Submitting User: | brettsp1 |
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