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Cell. 2018 Jan 25;172(3):590-604.e13. doi: 10.1016/j.cell.2017.12.032.

Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules.

Author information

1
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92039, USA.
2
Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
3
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
4
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
5
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
6
Neuromuscular & Movement Disorders, Biogen, Cambridge, MA 02142, USA.
7
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
8
Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada; Division of Experimental Medicine, McGill University, Montréal, QC H3A 1A3, Canada.
9
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92039, USA; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; Molecular Engineering Laboratory, A(∗)STAR, Singapore 138673, Singapore. Electronic address: geneyeo@ucsd.edu.

Abstract

Stress granules (SGs) are transient ribonucleoprotein (RNP) aggregates that form during cellular stress and are increasingly implicated in human neurodegeneration. To study the proteome and compositional diversity of SGs in different cell types and in the context of neurodegeneration-linked mutations, we used ascorbate peroxidase (APEX) proximity labeling, mass spectrometry, and immunofluorescence to identify ∼150 previously unknown human SG components. A highly integrated, pre-existing SG protein interaction network in unstressed cells facilitates rapid coalescence into larger SGs. Approximately 20% of SG diversity is stress or cell-type dependent, with neuronal SGs displaying a particularly complex repertoire of proteins enriched in chaperones and autophagy factors. Strengthening the link between SGs and neurodegeneration, we demonstrate aberrant dynamics, composition, and subcellular distribution of SGs in cells from amyotrophic lateral sclerosis (ALS) patients. Using three Drosophila ALS/FTD models, we identify SG-associated modifiers of neurotoxicity in vivo. Altogether, our results highlight SG proteins as central to understanding and ultimately targeting neurodegeneration.

KEYWORDS:

RNA-binding proteins; amyotrophic lateral sclerosis; granules; heat shock; motor neuron disease; neurodegeneration; phase separation; ribonucleoprotein; stress

PMID:
29373831
PMCID:
PMC5969999
DOI:
10.1016/j.cell.2017.12.032
[Indexed for MEDLINE]
Free PMC Article

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