1. Spatiotemporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis
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Paul A. Anderson, Tamar Geiger, Aviad Siany, Sarah Hofmann, Jacob H. Hanna, Tali Dadosh, Nancy Kedersha, Yehuda M. Danino, Thomas Moens, Yifat Merbl, Tsviya Olender, Pavel Ivanov, Chen Eitan, Johnathan Cooper-Knock, Adrian Higginbottom, Beata Toth Cohen, Revital Ravid, Natalia Rivkin, Vivek M. Advani, Daoud Sheban, Ludo Van Den Bosch, Claire L. Riggs, Nir Cohen, Naama Knafo, Eran Hornstein, Hagai Marmor-Kollet, and Yoseph Addadi more...
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Proteomics ,Biochemistry & Molecular Biology ,SUMO protein ,PROTEIN ,RNA-binding protein ,ORGANIZATION ,Biology ,Cytoplasmic Granules ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Stress granule ,Cell Line, Tumor ,medicine ,Animals ,Drosophila Proteins ,Humans ,INTERACTION NETWORKS ,PHOSPHORYLATION ,Molecular Biology ,FUS ,030304 developmental biology ,0303 health sciences ,Science & Technology ,C9orf72 Protein ,Stress granule disassembly ,COMPONENTS ,Neurodegeneration ,Amyotrophic Lateral Sclerosis ,Sumoylation ,Cell Biology ,Dipeptides ,medicine.disease ,Cell biology ,DROSOPHILA ,Drosophila melanogaster ,EXPANSIONS ,Cytoplasm ,Small Ubiquitin-Related Modifier Proteins ,AUTOPHAGY ,Life Sciences & Biomedicine ,030217 neurology & neurosurgery ,Function (biology) ,PHASE-SEPARATION - Abstract
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. ispartof: MOLECULAR CELL vol:80 issue:5 pages:876-+ ispartof: location:United States status: published more...
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