PKR-dependent cytosolic cGAS foci are necessary for intracellular DNA sensing
PKR-dependent cytosolic cGAS foci are necessary for intracellular DNA sensing
复制标题
PKR 依赖性胞质 cGAS 焦点对于细胞内 DNA 传感是必需的
DOI：
10.1126/scisignal.aav7934
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发表时间：
2019-11-26
影响因子：
7.3
通讯作者：
Guo, Fei
中科院分区：
文献类型：
--
作者：
Hu, Siqi;Sun, Hong;Guo, Fei
环鸟苷酸 - 腺苷酸合成酶（cGAS）是入侵病原体的胞质DNA以及受损细胞器的主要传感器。cGAS的激活促进液 - 液相分离以及无膜细胞质结构的形成。在此，我们发现cGAS与G3BP1结合，G3BP1是一种参与应激颗粒形成的双链核酸解旋酶。G3BP1的缺失阻断了亚细胞cGAS的凝聚，并抑制了细胞对细胞内DNA和DNA病毒颗粒的干扰素反应。此外，与蛋白激酶R（PKR）的RNA依赖性关联促进了G3BP1焦点形成以及cGAS依赖性干扰素反应。总之，这些结果表明PKR促进了人细胞中cGAS的DNA传感功能所必需的依赖G3BP1的无膜细胞质结构的形成。这些数据表明，核酸传感通路之间存在一种先前未被重视的联系，这种联系需要特殊亚细胞结构的形成。
Intracellular DNA provokes cytoplasmic cGAS condensation, which requires the helicase G3BP1 and the RNA-dependent kinase PKR. Stronger together Aberrant intracellular recognition of self-DNA is controlled by the spatial restriction of the DNA sensor cGAS. To define the interactions that may control cGAS subcellular localization, Hu et al. used mass spectrometry and immunoprecipitation to confirm that endogenous cGAS bound to the nucleotide helicase G3BP1, which is involved in stress granule formation. After DNA stimulation of human cells, cGAS associated in an RNA-dependent manner with G3BP1 and was found in cytoplasmic foci that also contained mRNA and the RNA-dependent kinase PKR. Formation of cytoplasmic cGAS condensates necessary for DNA-stimulated type I interferon production required G3BP1 and PKR activity. Together, these data suggest that G3BP1 cytoplasmic foci act as hubs that may coordinate DNA and RNA nucleic acid sensing. Cyclic GMP-AMP synthase (cGAS) is a major sensor of cytosolic DNA from invading pathogens and damaged cellular organelles. Activation of cGAS promotes liquid-like phase separation and formation of membraneless cytoplasmic structures. Here, we found that cGAS bound G3BP1, a double-stranded nucleic acid helicase involved in the formation of stress granules. Loss of G3BP1 blocked subcellular cGAS condensation and suppressed the interferon response to intracellular DNA and DNA virus particles in cells. Furthermore, an RNA-dependent association with PKR promoted G3BP1 foci formation and cGAS-dependent interferon responses. Together, these results indicate that PKR promotes the formation of G3BP1-dependent, membraneless cytoplasmic structures necessary for the DNA-sensing function of cGAS in human cells. These data suggest that there is a previously unappreciated link between nucleic acid sensing pathways, which requires the formation of specialized subcellular structures.