ATPase modulated stress granules contain a diverse proteome and substructure

By Saumya Jain, Joshua R. Wheeler, R. Walters, A. Agrawal, A. Barsic, R. Parker. Cell, 2016

1,422 citations recorded by the source corpus.

SUMMARY Stress granules are mRNA-protein granules that form when translation initiation is limited and are related to pathological granules in various neurodegenerative diseases. Super-resolution microscopy reveals stable substructures referred to as cores within stress granules that can be purified. Proteomic analysis of stress granule cores reveals a dense network of protein-protein interactions, links between stress granules and human diseases, and identifies ATP-dependent helicases and protein remodelers as conserved stress granule components. ATP is required for stress granule assembly and dynamics. Moreover, multiple ATP-driven machines affect stress granules differently; with the CCT complex inhibiting stress granule assembly, while the MCM and RVB complexes promote stress granule persistence. Our observations suggest that stress granules contain a stable core structure surrounded by a dynamic shell with assembly, disassembly and transitions between the core and shell modulated by numerous protein and RNA remodeling complexes.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/37296ce2044fb7c28ca61b3fb3ba9cf0be0d82d8

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Citations in the corpus

Charge pattern matching as a ‘fuzzy’ mode of molecular recognition for the functional phase separations of intrinsically disordered proteins (2017, background): “cal development bears on the sequence dependence of multicomponent phase separation in the cell. However, because the cellular processes involve many species of biomolecules and are extremely complex [27,71], development of treatments much more elaborated than our simple theories will be needed for ”
Competing protein-RNA interaction networks control multiphase intracellular organization (2020, positive): “Competition betweenProtein-Protein InteractionNodes Encodes Multiphase Condensation Consistent with previous studies (Cirillo et al., 2020; Jain et al., 2016; Niewidok et al., 2018), super-resolution live cell microscopy revealed the presence of micro-phases (‘‘cores’’) within SGs (Figure 6G), which”
Stress-triggered phase separation is an adaptive, evolutionarily tuned response (2017, background): “…hypoxia, treatment with metabolic inhibitors, and other unfavorable changes trigger stress granule formation across a wide array of organisms (Cherkasov 1028 Cell 168, 1028–1040, March 9, 2017 ª 2017 Elsevier Inc. et al., 2013; Farny et al., 2009; Jain et al., 2016; Kroschwald et al., 2015).”
Intrinsically disordered regions contribute promiscuous interactions to RNP granule assembly (2017, background): “However, IDRs are enriched in RNP granule proteins (Decker et al., 2007; Jain et al., 2016; Kato et al., 2012; King et al., 2012; Reijns et al., 2008), and IDRs can play a role in RNP granule assembly (e.g. Decker et al., 2007; Gilks et al., 2004; Wang et al., 2014).”
Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules (2018, background): “It is among the most disordered proteins in the human proteome, with 99.4% of its 1,087 amino acids considered to fall within IDRs (Figure S5D), suggesting a potential for UBAP2L to undergo LLPS. Interestingly, while inducible expression of an UBAP2L-mCherry fusion protein recapitulated endogenous U”
Liquid phase condensation in cell physiology and disease (2017, background): “These findings could help explain the coreshell structures observed in several intracellular condensates, including paraspeckles (82), PML bodies (83), and stress granules (62), although in the latter case, an ordered assembly model has been proposed (84).”
Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity (2017, neutral): “FUS-containing membraneless organelles are not homogeneous structures composed of one protein and one RNA (Kato et al , 2012; Jain et al , 2016).”
Compositional Control of Phase-Separated Cellular Bodies (2016, positive): “Finally, several cellular bodies contain subcompartments (condensed phases within the primary condensed phase) and thus are not simple droplet/bulk systems (Brangwynne et al., 2011; Feric et al., 2016; Jain et al., 2016; Wang et al., 2014).”
High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. (2018, background): “As both NMF and SAFE prey annotations supported and complemented each other, we defined a final list of 144 proteins as our ‘‘core’’ SG and PB proteome, which largely overlapped with previously published mRNA-binding and SG proteomes (Table S8; STAR Methods; Baltz et al., 2012; Castello et al., 2012”
Protein Phase Separation: A New Phase in Cell Biology (2018, background): “Moreover, the proteins associated with membraneless organelles often possess RNA-binding domains or motifs [9,23] and RNA promotes phase separation of various RBPs [9,10,14,16,58–60] (Figure 2C).”
The stress granule transcriptome reveals principles of mRNA accumulation in stress granules (2017, positive): “One simple explanation is that the staining of both proteins and RNAs in the shell region of SGs (Jain et al., 2016) is due to mRNAs of sufﬁcient length that they have portions residing within the core region and thus co-purify with cores after cell lysate.”
FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions (2018, background): “…Terminals Outside of the nucleus, TNPO1 colocalizes with some cytoplasmic RNA granules, where it coexists with FUS, purine-rich element binding protein A (Pur-a, which modulates toxicity of ALS-associated FUS mutants), and Staufen-1 (a marker of neuronal transport granules) (Jain et al., 2016).”
Spatiotemporal control of intracellular phase transitions using light-activated optoDroplets (2016, positive): “For example, both nucleoli and stress granules have recently been reported to have a core-shell structure, where gel-like cores are engulfed by a dynamic liquid-like shell ((Jain et al., 2016), (Feric et al., 2016)).”