Regulation of cGAS activity through RNA-mediated phase separation
Regulation of cGAS activity through RNA-mediated phase separation
Abstract Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA (dsDNA) sensor that functions in the innate immune system. Upon binding dsDNA in the cytoplasm, cGAS and dsDNA form phase-separated aggregates in which cGAS catalyzes synthesis of 2’3’-cyclic GMP-AMP that subsequently triggers a STING-dependent, type I IFN response. Here, we showed that cytoplasmic RNAs, especially tRNAs, regulate cGAS activity. We discovered that RNAs did not activate cGAS but rather promoted phase separation in vitro. In cells, cGAS colocalized with RNAs and formed phase-separated granules even in the absence of cytoplasmic dsDNA. An Opti-prep gradient analysis of cell lysates showed that the endogenous cGAS was associated with cytoplasmic RNAs in an aggregative form. Further in vitro assays showed that RNAs compete for binding of cGAS with dsDNA and inhibit cGAS activity when the dsDNA concentration is high and promote the formation of phase separations and enhance cGAS activity when the dsDNA concentration is low. Thus, cytoplasmic RNAs regulate cGAS activity by interfering with formation of cGAS-containing aggregates.
Chen Silian、Zhu Deyu、Rong Miao、Lv Yun、Xiang Ye
Center for Infectious Disease Research, Beijing Frontier Research Center for Biological Structure & Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityCenter for Infectious Disease Research, Beijing Frontier Research Center for Biological Structure & Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityCenter for Infectious Disease Research, Beijing Frontier Research Center for Biological Structure & Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University
基础医学分子生物学生物化学
Chen Silian,Zhu Deyu,Rong Miao,Lv Yun,Xiang Ye.Regulation of cGAS activity through RNA-mediated phase separation[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/2020.09.27.316166.点此复制
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