Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner

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.

RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

“…Beyond compartmentalization, numerous vital roles have been recently associated with biomolecular condensates, including cell signaling [2,7], formation of super-enhancers [8], genome organization [9][10][11][12], and aiding cells to sense and react to environmental changes [13] among many others [14][15][16][17]. Within the extensive class of biomolecules that can undergo phase separation at physiological conditions, RNA-binding proteins (RBPs) such as FUS [18][19][20], hnRNPA1 [21,22], TDP-43 [23][24][25], TAF-15 [26,27], G3BP1 [28][29][30][31] or EWSR1 [26,27,32], have been widely investigated due to their implications in the stability of stress granules [33,34], P granules [1,35,36] or RNA granules/bodies [37][38][39]important phase-separated organelles within cells.…”

Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression

“…Single-cell profiling has been used to examine the gene expression programs activated during 3D breast epithelial acinar morphogenesis [36]. The global analysis identifies JUND transcription factor, as well as a transcript cluster containing genes that have strong connection with oxidative stress responses and ER stress (SLC25A28 [37], BCL2L13 [38], FAF2 [39], PRDX4 [40], FAM120A [41], SERP1 [42], and FOXO1). SLC25A28, a mitochondrial iron importer, was reported to mediate metabolic reprograming in tumorigenesis [37].…”

“…In response to environmental stressors, stress granules arise in the cytoplasm and are disassembled after the stress is relieved. The ER-associated protein FAF2 (FAS-associated factor 2) recruits stress granules and promotes their disassembly [39]. PRDX4 is the only PRDX (peroxiredoxins) family member located within the ER.…”

Managing stress granule disassembly with ubiquitin and its cousin

“…Here, we highlight very recent elegant recent work by the Taylor laboratory providing novel insight into how cells exploit the ubiquitin system for recovery from heat stress. 1 , 2 …”

“…To better define stress-induced ubiquitylation events Maxwell et al 2 set out with an unbiased system-wide analysis of the cellular ubiquitylome in response to several stress stimuli: heat shock, oxidative stress (arsenite), osmotic stress (sorbitol), ultraviolet irradiation, and proteasome inhibition. Affinity enrichment of ubiquitylated proteins followed by mass-spectrometry revealed common ubiquitylation events as part of a general stress response.…”