Calcium signaling from damaged lysosomes induces cytoprotective stress granules

Jacob Duran; Jay E Salinas; Rui Ping Wheaton; Suttinee Poolsup; Lee Allers; Monica Rosas-Lemus; Li Chen; Qiuying Cheng; Jing Pu; Michelle Salemi; Brett Phinney; Pavel Ivanov; Alf Håkon Lystad; Kiran Bhaskar; Jaya Rajaiya; Douglas J Perkins; Jingyue Jia

doi:10.1038/s44318-024-00292-1

Calcium signaling from damaged lysosomes induces cytoprotective stress granules

EMBO J. 2024 Nov 12. doi: 10.1038/s44318-024-00292-1. Online ahead of print.

Authors

Jacob Duran^#^{1

2}, Jay E Salinas^#^{1

2}, Rui Ping Wheaton^#^{1

2}, Suttinee Poolsup^{1

2}, Lee Allers^{2

3}, Monica Rosas-Lemus^{2

3}, Li Chen^{2

3}, Qiuying Cheng¹, Jing Pu³, Michelle Salemi⁴, Brett Phinney⁴, Pavel Ivanov⁵, Alf Håkon Lystad⁶, Kiran Bhaskar^{3

7}, Jaya Rajaiya³, Douglas J Perkins¹, Jingyue Jia^{8

9}

Affiliations

¹ Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, 87106, USA.
² Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, Albuquerque, NM, 87106, USA.
³ Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87106, USA.
⁴ Proteomics Core Facility, University of California Davis Genome Center, University of California, Davis, CA, 95616, USA.
⁵ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; HMS Initiative for RNA Medicine, Boston, MA, 02115, USA.
⁶ Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
⁷ Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87106, USA.
⁸ Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, 87106, USA. JJia@salud.unm.edu.
⁹ Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, Albuquerque, NM, 87106, USA. JJia@salud.unm.edu.

^# Contributed equally.

PMID: 39533058
DOI: 10.1038/s44318-024-00292-1

Abstract

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-2^ORF3a, 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.

Keywords: ALG2-ALIX; Calcium-dependent Pathway; Lysosomal Damage; PACT-PKR-eIF2α; Stress Granules.

Abstract

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