G3BP1 Is a Tunable Switch that Triggers Phase Separation to Assemble Stress Granules
Authors: Yang, Peiguo; Mathieu, Cecile; Kolaitis, Regina-Maria; Zhang, Peipei; Messing, James; Yurtsever, Ugur; Yang, Zemin; Wu, Jinjun; Li, Yuxin; Pan, Qingfei; Yu, Jiyang; Martin, Erik W.; Mittag, Tanja; Kim, Hong Joo; Taylor, J. Paul
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.
Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Authors: Park, Ye-Jin; Choi, Dong Wook; Cho, Sang Woo; Han, Jaeseok; Yang, Siyoung; Choi, Cheol Yong
Stress granules are membraneless organelles composed of numerous components including ribonucleoproteins. The stress granules are characterized by a dynamic complex assembly in response to various environmental stressors, which has been implicated in the coordinated regulation of diverse biological pathways, to exert a protective role against stress-induced cell death. Here, we show that stress granule formation is induced by morusin, a novel phytochemical displaying antitumor capacity through barely known mechanisms. Morusin-mediated induction of stress granules requires activation of protein kinase R (PKR) and subsequent eIF2 alpha phosphorylation. Notably, genetic inactivation of stress granule formation mediated by G3BP1 knockout sensitized cancer cells to morusin treatment. This protective function against morusin-mediated cell death can be attributed at least in part to the sequestration of receptors for activated C kinase-1 (RACK1) within the stress granules, which reduces caspase-3 activation. Collectively, our study provides biochemical evidence for the role of stress granules in suppressing the antitumor capacity of morusin, proposing that morusin treatment, together with pharmacological inhibition of stress granules, could be an efficient strategy for targeting cancer.