Journal
MOLECULAR CELL
Volume 80, Issue 5, Pages 876-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2020.10.032
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Funding
- Bloomington Drosophila Stock Center (National Institutes of Health) [P40OD018537]
- Radala Foundation (project Proteomic mapping of SG disassembly processes suggests a potential neuroprotective role of SUMOylation in C9orf72-associated ALS'')
- Minerva Foundation (project Regulation of stress granules disassembly'')
- Federal German Ministry for Education and Research, ISF Legacy grant [828/17]
- Target ALS grant [118945]
- European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC [617351]
- Israel Science Foundation [135/16]
- ALS Therapy Alliance
- AFM-Telethon [20576]
- Motor Neurone Disease Association (UK)
- Thierry Latran Foundation for ALS Research
- ERA-Net for Research Programmes on Rare Diseases (FP7)
- Israel Ministry of Trade and Industry
- Y. Leon Benoziyo Institute for Molecular Medicine
- Benoziyo Center Neurological Disease
- Kekst Family Institute for Medical Genetics
- David and Fela Shapell Family Center for Genetic Disorders Research
- Crown Human Genome Center
- Nathan, Shirley, Philip, and Charlene Vener New Scientist Fund
- Julius and Ray Charlestein Foundation
- Fraida Foundation
- Wolfson Family Charitable Trust
- Abney Foundation
- Merck
- estate of Fannie Sherr
- estate of Lola Asseof
- estate of Lilly Fulop
- estate of E. and J. Moravitz
- EU Horizon 2020 Programme for Research and Innovation Marie SklodowskaCurie actions [845692]
- National Institutes of Health [P40OD018537, R35 GM126901, RO1 GM126150]
- Marie Curie Actions (MSCA) [845692] Funding Source: Marie Curie Actions (MSCA)
- European Research Council (ERC) [617351] Funding Source: European Research Council (ERC)
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Stress granules (SGs) are cytoplasmic assemblies of proteins and non-translating mRNAs. Whereas much has been learned about SG formation, a major gap remains in understanding the compositional changes SGs undergo during normal disassembly and under disease conditions. Here, we address this gap by proteomic dissection of the SG temporal disassembly sequence using multi-bait APEX proximity proteomics. We discover 109 novel SG proteins and characterize distinct SG substructures. We reveal dozens of disassembly-engaged proteins (DEPs), some of which play functional roles in SG disassembly, including small ubiquitin-like modifier (SUMO) conjugating enzymes. We further demonstrate that SUMOylation regulates SG disassembly and SG formation. Parallel proteomics with amyotrophic lateral sclerosis (ALS)-associated C9ORF72 dipeptides uncovered attenuated DEP recruitment during SG disassembly and impaired SUMOylation. Accordingly, SUMO activity ameliorated C9ORF72-ALS-related neurodegeneration in Drosophila. By dissecting the SG spatiotemporal proteomic landscape, we provide an in-depth resource for future work on SG function and reveal basic and disease-relevant mechanisms of SG disassembly.
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