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

49 Pages Posted: 19 Feb 2020 Publication Status: Review Complete

See all articles by Hagai Marmor Kollet

Hagai Marmor Kollet

Weizmann Institute of Science - Department of Molecular Genetics

Aviad Siany

Weizmann Institute of Science - Department of Molecular Genetics

Nancy Kedersha

Harvard University - Division of Rheumatology, Immunology and Allergy

Naama Knafo

Tel Aviv University - Department of Human Molecular Genetics and Biochemistry

Natalia Rivkin

Weizmann Institute of Science - Department of Molecular Genetics

Yehuda M. Danino

Weizmann Institute of Science - Department of Molecular Genetics

Tsviya Olender

Weizmann Institute of Science - Department of Molecular Genetics

Nir Cohen

Weizmann Institute of Science - Department of Molecular Genetics

Thomas Moens

KU Leuven - Experimental Neurology

Adrian Higginbottom

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Johnathan Cooper-Knock

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Chen Eitan

Weizmann Institute of Science - Department of Molecular Genetics

Beata Toth Cohen

Weizmann Institute of Science - Department of Molecular Genetics

Ludo Van Den Bosch

KU Leuven - Experimental Neurology

Paul Anderson

Harvard University - Division of Rheumatology, Immunology and Allergy

Pavel Ivanov

Harvard University - Division of Rheumatology, Immunology and Allergy

Tamar Geiger

Tel Aviv University - Department of Human Molecular Genetics and Biochemistry

Eran Hornstein

Weizmann Institute of Science - Department of Molecular Genetics

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Abstract

Cytoplasmic stress granules (SG) form in response to a variety of cellular stresses by phase-separation of proteins associated with non-translating mRNAs. SG provide insight into the biology of neurodegeneration, including amyotrophic lateral sclerosis (ALS) because they approximate some of the molecular conditions for nucleation of insoluble aggregates in neuropathological inclusions. Whereas much has been learned about SG formation, a major gap remains in understanding the compositional changes SG undergo during normal disassembly and under disease conditions. Here, we address this gap by proteomic dissection of SG temporal disassembly sequence, using multi-bait APEX proximity-proteomics. We discover 109 novel SG-proteins and characterize at proteomic resolution two biophysically distinct SG substructures. We further demonstrate that dozens of additional proteins are recruited to SG specifically during disassembly, indicating that it is a highly regulated process. The involved proteins link SG disassembly, to mitochondrial biology and the cytoskeleton. Parallel analysis with C9ORF72-associated dipeptides, which are found in patients with ALS and frontotemporal dementia, demonstrated compositional changes in SG during the course of disassembly and focused our attention on the roles SUMOylation in SG disassembly. We demonstrate that broad SUMOylation of SG-proteins is required for SG disassembly and is impaired by C9ORF72-associated dipeptides, representing an unexplored potential molecular mechanism of neurodegeneration. Altogether, out study fundamentally increases the knowledge about SG composition in human cells by dissecting the SG spatio-temporal proteomic landscape, provides an in-depth resource for future work on SG function and reveals basic and disease-relevant mechanisms of SG disassembly.

Suggested Citation

Marmor Kollet, Hagai and Siany, Aviad and Kedersha, Nancy and Knafo, Naama and Rivkin, Natalia and Danino, Yehuda M. and Olender, Tsviya and Cohen, Nir and Moens, Thomas and Higginbottom, Adrian and Cooper-Knock, Johnathan and Eitan, Chen and Toth Cohen, Beata and Van Den Bosch, Ludo and Anderson, Paul and Ivanov, Pavel and Geiger, Tamar and Hornstein, Eran, Spatio-Temporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis. Available at SSRN: https://ssrn.com/abstract=3537940 or http://dx.doi.org/10.2139/ssrn.3537940
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Hagai Marmor Kollet

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Aviad Siany

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Nancy Kedersha

Harvard University - Division of Rheumatology, Immunology and Allergy ( email )

United States

Naama Knafo

Tel Aviv University - Department of Human Molecular Genetics and Biochemistry ( email )

Tel Aviv, 69978
Israel

Natalia Rivkin

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Yehuda M. Danino

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Tsviya Olender

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Nir Cohen

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Thomas Moens

KU Leuven - Experimental Neurology

Oude Markt 13 - bus 5005
Leuven, 3000
Belgium

Adrian Higginbottom

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Johnathan Cooper-Knock

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN) ( email )

385a Glossop Road
Sheffield
United Kingdom

Chen Eitan

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Beata Toth Cohen

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Ludo Van Den Bosch

KU Leuven - Experimental Neurology ( email )

Oude Markt 13 - bus 5005
Leuven, 3000
Belgium

Paul Anderson

Harvard University - Division of Rheumatology, Immunology and Allergy

United States

Pavel Ivanov

Harvard University - Division of Rheumatology, Immunology and Allergy

United States

Tamar Geiger

Tel Aviv University - Department of Human Molecular Genetics and Biochemistry ( email )

Tel Aviv, 69978
Israel

Eran Hornstein (Contact Author)

Weizmann Institute of Science - Department of Molecular Genetics

Rehovot, 7610001
Israel

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