Lysosomal damage induces stress granule (SG) formation. However, the importance of SGs in determining cell fate and the precise mechanisms that mediate SG formation in response to lysosomal damage remain unclear. Here, we describe a novel calcium-dependent pathway controlling SG formation, which promotes cell survival during lysosomal damage. Mechanistically, the calcium-activated protein ALIX transduces lysosomal damage signals to SG formation by controlling eIF2α phosphorylation after sensing calcium leakage. ALIX enhances eIF2α phosphorylation by promoting the association between PKR and its activator PACT, with galectin-3 inhibiting this interaction; these regulatory events occur on damaged lysosomes. We further find that SG formation plays a crucial role in promoting cell survival upon lysosomal damage caused by factors such as SARS-CoV-2ORF3a, adenovirus, malarial pigment, proteopathic tau, or environmental hazards. Collectively, these data provide insights into the mechanism of SG formation upon lysosomal damage and implicate it in diseases associated with damaged lysosomes and SGs.

中文翻译：

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来自受损溶酶体的钙信号传导诱导细胞保护应激颗粒。


溶酶体损伤诱导应激颗粒 （SG） 形成。然而，SG 在决定细胞命运中的重要性以及介导 SG 形成以响应溶酶体损伤的确切机制仍不清楚。在这里，我们描述了一种控制 SG 形成的新型钙依赖性途径，该途径在溶酶体损伤期间促进细胞存活。从机制上讲，钙活化蛋白 ALIX 在感应到钙泄漏后通过控制 eIF2α 磷酸化，将溶酶体损伤信号转导到 SG 形成。ALIX 通过促进 PKR 与其激活剂 PACT 之间的结合来增强 eIF2α 磷酸化，而半乳糖凝集素-3 抑制这种相互作用;这些调节事件发生在受损的溶酶体上。我们进一步发现，SG 形成在由 SARS-CoV-2ORF3a、腺病毒、疟疾色素、蛋白病性 tau 或环境危害等因素引起的溶酶体损伤后促进细胞存活方面起着至关重要的作用。总的来说，这些数据为溶酶体损伤时 SG 形成的机制提供了见解，并将其与溶酶体和 SG 受损相关的疾病有关。