Abstract
Stress granules are dynamic, reversible condensates composed of RNA and protein that assemble in eukaryotic cells in response to a variety of stressors and are normally disassembled after stress is removed. The composition and assembly of stress granules is well understood, but little is known about the mechanisms that govern disassembly. Impaired disassembly has been implicated in some diseases including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Using cultured human cells, we found that stress granule disassembly was context-dependent: Specifically in the setting of heat shock, disassembly required ubiquitination of G3BP1, the central protein within the stress granule RNA-protein network. We found that ubiquitinated G3BP1 interacted with the endoplasmic reticulum–associated protein FAF2, which engaged the ubiquitin-dependent segregase p97/VCP (valosin-containing protein). Thus, targeting of G3BP1 weakened the stress granule–specific interaction network, resulting in granule disassembly.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Autophagy
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Blood Proteins / metabolism*
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Cell Line, Tumor
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Cytoplasmic Granules / metabolism*
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DNA Helicases / chemistry
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DNA Helicases / genetics
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DNA Helicases / metabolism*
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Endoplasmic Reticulum / metabolism
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HEK293 Cells
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Heat-Shock Response*
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Humans
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Intracellular Membranes / metabolism
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Membrane Proteins / metabolism*
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Mutation
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Poly-ADP-Ribose Binding Proteins / chemistry
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Poly-ADP-Ribose Binding Proteins / genetics
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Poly-ADP-Ribose Binding Proteins / metabolism*
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Polyubiquitin / metabolism
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Protein Domains
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Proteolysis
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RNA Helicases / chemistry
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RNA Helicases / genetics
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RNA Helicases / metabolism*
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RNA Recognition Motif Proteins / chemistry
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RNA Recognition Motif Proteins / genetics
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RNA Recognition Motif Proteins / metabolism*
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Ubiquitinated Proteins / chemistry
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Ubiquitinated Proteins / metabolism*
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Ubiquitination
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Valosin Containing Protein / metabolism*
Substances
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Blood Proteins
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FAF2 protein, human
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Membrane Proteins
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Poly-ADP-Ribose Binding Proteins
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RNA Recognition Motif Proteins
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Ubiquitinated Proteins
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Polyubiquitin
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DNA Helicases
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G3BP1 protein, human
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RNA Helicases
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VCP protein, human
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Valosin Containing Protein