Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 44, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2207975119
Keywords
stress granules; liquid-liquid phase separation; RNA-binding proteins Caprin-1; G3BP1
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Funding
- Ministry of Science and Technology of China [2019YFA0904100, 2017YFA0504900]
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The study reveals the mechanism of stress granule (SGs) formation, demonstrating the interaction of G3BP1 protein with Caprin-1 and USP10 to facilitate or suppress SG formation. The N- and C-terminal domains of Caprin-1 play opposing roles in regulating SG formation.
Stress granules (SGs) are cytoplasmic biomolecular condensates containing proteins and RNAs in response to stress. Ras-GTPase-activating protein binding protein 1 (G3BP1) is a core SG protein. Caprin-1 and ubiquitin specific peptidase 10 (USP10) interact with G3BP1, facilitating and suppressing SG formation, respectively. The crystal structures of the nuclear transport factor 2-like (NTF2L) domain of G3BP1 in complex with the G3BP1-interacting motif (GIM) of Caprin-1 and USP10 show that both GIMs bind to the same hydrophobic pocket of G3BP1. Moreover, both GIMs suppressed the liquid-liquid phase separation (LLPS) of G3BP1, suggesting that Caprin-1 likely facilitates SG formation via other mechanisms. Thus, we dissected various domains of Caprin-1 and investigated their role in LLPS in vitro and SG formation in cells. The C-terminal domain of Caprin-1 underwent spontaneous LLPS, whereas the N-terminal domain and GIM of Caprin-1 suppressed LLPS of G3BP1. The opposing effect of the N- and C-terminal domains of Caprin-1 on SG formation were demonstrated in cells with or without the endogenous Caprin-1. We propose that the N- and C-terminal domains of Caprin-1 regulate SG formation in a yin and yang fashion, mediating the dynamic and reversible assembly of SGs.
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