G3BP1 Is a Tunable Switch that Triggers Phase Separation to Assemble Stress Granules.

1. Cell. 2020 Apr 16;181(2):325-345.e28. doi: 10.1016/j.cell.2020.03.046. G3BP1 Is a Tunable Switch that Triggers Phase Separation to Assemble Stress Granules. Yang P(1), Mathieu C(2), Kolaitis RM(1), Zhang P(1), Messing J(2), Yurtsever U(3), Yang Z(1), Wu J(1), Li Y(4), Pan Q(5), Yu J(5), Martin EW(6), Mittag T(6), Kim HJ(1), Taylor JP(7). Author information: (1)Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (2)Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. (3)Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Graduate School of Structure and Dynamics of Living Systems, Université Paris-Saclay, Gif-sur-Yvette, 91190, France. (4)Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (5)Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (6)Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (7)Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: jpaul.taylor@stjude.org. Comment in Cell. 2020 Apr 16;181(2):228-230. doi: 10.1016/j.cell.2020.03.056. The mechanisms underlying ribonucleoprotein (RNP) granule assembly, including the basis for establishing and maintaining RNP granules with distinct composition, are unknown. One prominent type of RNP granule is the stress granule (SG), a dynamic and reversible cytoplasmic assembly formed in eukaryotic cells in response to stress. Here, we show that SGs assemble through liquid-liquid phase separation (LLPS) arising from interactions distributed unevenly across a core protein-RNA interaction network. The central node of this network is G3BP1, which functions as a molecular switch that triggers RNA-dependent LLPS in response to a rise in intracellular free RNA concentrations. Moreover, we show that interplay between three distinct intrinsically disordered regions (IDRs) in G3BP1 regulates its intrinsic propensity for LLPS, and this is fine-tuned by phosphorylation within the IDRs. Further regulation of SG assembly arises through positive or negative cooperativity by extrinsic G3BP1-binding factors that strengthen or weaken, respectively, the core SG network. Copyright © 2020 Elsevier Inc. All rights reserved. DOI: 10.1016/j.cell.2020.03.046 PMCID: PMC7448383 PMID: 32302571 [Indexed for MEDLINE] Conflict of interest statement: Declaration of Interests J.P.T. is a consultant for 5AM and Third Rock Ventures.