Yin and yang regulation of stress granules by Caprin-1

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 44; p. e2207975119
• Main Authors: Song, Dan, Kuang, Lisha, Yang, Lin, Wang, Lei, Li, Hao, Li, Xiu, Zhu, Zhimin, Shi, Chaowei, Zhu, Haining, Gong, Weimin
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01.11.2022
• Subjects: Biological Sciences; Crystal structure; Cytoplasmic Granules - metabolism; DNA Helicases - metabolism; Granular materials; GTPase-Activating Proteins - metabolism; Hydrophobicity; Liquid phases; Nuclear transport; Peptidase; Peptidases; Phase separation; Poly-ADP-Ribose Binding Proteins - metabolism; Proteins; RNA Helicases - metabolism; RNA Recognition Motif Proteins - metabolism; Stress Granules; Ubiquitin; Ubiquitin-Specific Proteases - metabolism; Caprin-1; stress granules; RNA-binding proteins; liquid–liquid phase separation; G3BP1
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2207975119

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.