Spatiotemporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis

Hagai Marmor-Kollet, Aviad Siany, Nancy Kedersha, Naama Knafo, Natalia Rivkin, Yehuda M. Danino, Thomas G. Moens, Tsviya Olender, Daoud Sheban, Nir Cohen, Tali Dadosh, Yoseph Addadi, Revital Ravid, Chen Eitan, Beata Toth Cohen, Sarah Hofmann, Claire L. Riggs, Vivek M. Advani, Adrian Higginbottom, Johnathan Cooper-KnockJacob H. Hanna, Yifat Merbl, Ludo Van Den Bosch, Paul Anderson, Pavel Ivanov, Tamar Geiger, Eran Hornstein

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)876-891.e6
JournalMolecular Cell
Volume80
Issue number5
DOIs
StatePublished - 3 Dec 2020

Keywords

  • ALS
  • APEX
  • RNA binding proteins
  • amyotrophic lateral sclerosis
  • condensates
  • membraneless organelles
  • neurodegeneration
  • phase separation
  • stress granules
  • sumoylation

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