Structural basis for nucleosome-mediated inhibition of cGAS activity  

作　　者：Duanfang Cao Xiaonan Han Xiaoyi Fan Rui-Ming Xu Xinzheng Zhang 

机构地区：[1]National Laboratory of Biomacromolecules,CAS Center for Excellence in Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Center for Biological Imaging,CAS Center for Excellence in Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China

出　　处：《Cell Research》2020年第12期1088-1097,共10页细胞研究（英文版）

基　　金：the National Key R&D Program of China(2017YFA0504700,2019YFA0508900);the Ministry of Science and Technology of China;the National Natural Science Foundation of China(31930069,31521002 and 31991162);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB37040101,XDB37010101).X.Z.received scholarships from the'National Thousand(Young)Talents Program,from the Office of Global Experts Recruitment in China.D.C.is sponsored by the Youth Innovation Promotion Association at the Chinese Academy of Sciences(2018124).

摘　　要：Activation of cyclic GMP-AMP synthase(cGAS)through sensing cytosolic double stranded DNA(dsDNA)plays a pivotal role in innate immunity against exogenous infection as well as cellular regulation under stress.Aberrant activation of cGAS induced by self-DNA is related to autoimmune diseases.cGAS accumulates at chromosomes during mitosis or spontaneously in the nucleus.Binding of cGAS to the nucleosome competitively attenuates the dsDNA-mediated cGAS activation,but the molecular mechanism of the attenuation is still poorly understood.Here,we report two cryo-electron microscopy structures of cGAS-nucleosome complexes.The structures reveal that cGAS interacts with the nucleosome as a monomer,forming 1:1 and 2:2 complexes,respectively.cGAS contacts the nucleosomal acidic patch formed by the H2A-H2B heterodimer through the dsDNA-binding site B in both complexes,and could interact with the DNA from the other symmetrically placed nucleosome via the dsDNA-binding site C in the 2:2 complex.The bound nucleosome inhibits the activation of cGAS through blocking the interaction of cGAS with ligand dsDNA and disrupting cGAS dimerization.R236A or R255A mutation of cGAS impairs the binding between cGAS and the nucleosome,and largely relieves the nucleosome-mediated inhibition of cGAS activity.Our study provides structural insights into the inhibition of cGAS activity by the nucleosome,and advances the understanding of the mechanism by which hosts avoid the autoimmune attack caused by cGAS.

关 键 词：complex. ACTIVATION COMPLEXES 

分 类 号：Q2[生物学—细胞生物学]