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

By Sebastian J. Markmiller, Sahar Soltanieh, Kari L. Server, Raymond H. Mak, Amit Fulzele, Gene W. Yeo. Cell, 2018

821 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/efbec8f4c895d0493fa990e4535dd74f5389036f

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Citations in the corpus

Competing protein-RNA interaction networks control multiphase intracellular organization (2020, neutral): “Despite this patterning and the known involvement of a complex network of RNA-binding proteins (RBPs) (Markmiller et al., 2018; Youn et al., 2018), studies indicate the essentiality of a single protein, G3BP, for RNA-dependent SG condensation (Guillén-Boixet et al., 2020 [this issue of Cell]; Bley…”
G3BP1 is a tunable switch that triggers phase separation to assemble stress granules (2020, neutral): “Specifically, nine proteins that are consistently reported in SGs (Jain et al., 2016; Markmiller et al., 2018) were absent from SGs seeded by G3BP1–2xAsh1 IDR, and recruitment of an additional four SG proteins was significantly reduced (Figure 6N, Table S3).”
OpenCell: proteome-scale endogenous tagging enables the cartography of human cellular organization (2022, background): “4C) that separate into granules upon stress conditions ( 56 – 59 ).”
A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA (2020, background): “Additionally, an APEX-based proteomic analysis of the G3BP1 stress granule protein found all three DF paralogs as interactors (Markmiller et al., 2018).”