Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion
Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion
复制标题
病毒外皮蛋白限制 cGAS-DNA 相分离以介导免疫逃避
DOI：
10.1016/j.molcel.2021.05.002
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发表时间：
2021-07-01
期刊：
影响因子：
16
通讯作者：
Gao, Pu
中科院分区：
文献类型：
--
作者：
Xu, Guangju;Liu, Chong;Gao, Pu
DNA诱导的环状GMP-AMP合成酶(CGAS)液-液相分离可触发检测病原体感染和促进先天免疫信号转导的有效反应。病原体是否以及如何操纵cGAS-DNA缩合来调节免疫逃避尚不清楚。我们报告了一个结构上相关的病毒被膜蛋白家族的鉴定，分别由ORF52和VP22代表，分别来自伽马和阿尔法疱疹病毒，它使用一种保守的机制来限制cGAS-DNA相分离。ORF52/VP22蛋白在体外和细胞内积聚并有效地破坏预先形成的cGAS-DNA凝聚。抑制过程依赖于DNA诱导的病毒蛋白的液-液分离，而不是与cGAS的直接相互作用。此外，病毒颗粒中携带的高度丰富的ORF52蛋白能够在感染早期靶向cGAS-DNA时相分离。我们的结果将ORF52/VP22型被膜蛋白定义为一类针对cGAS-DNA相分离的抑制剂家族，并展示了病毒如何克服先天免疫的机制。
DNA-induced liquid-liquid phase separation of cyclic GMP-AMP synthase (cGAS) triggers a potent response to detect pathogen infection and promote innate immune signaling. Whether and how pathogens manipulate cGAS-DNA condensation to mediate immune evasion is unknown. We report the identification of a structurally related viral tegument protein family, represented by ORF52 and VP22 from gamma-and alpha-herpesvirinae, respectively, that employs a conserved mechanism to restrict cGAS-DNA phase separation. ORF52/ VP22 proteins accumulate into, and effectively disrupt, the pre-formed cGAS-DNA condensation both in vitro and in cells. The inhibition process is dependent on DNA-induced liquid-liquid phase separation of the viral protein rather than a direct interaction with cGAS. Moreover, highly abundant ORF52 proteins carried within viral particles are able to target cGAS-DNA phase separation in early infection stage. Our results define ORF52/VP22-type tegument proteins as a family of inhibitors targeting cGAS-DNA phase separation and demonstrate a mechanism for how viruses overcome innate immunity.