Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion

• Published in: Molecular cell 2021-07, Vol.81 (13), p.2823-2837.e9
• Main Authors: Xu, Guangjun, Liu, Chong, Zhou, Sheng, Li, Quanjin, Feng, Yun, Sun, Panpan, Feng, Han, Gao, Yina, Zhu, Jingpeng, Luo, Xiu, Zhan, Qi, Liu, Songqing, Zhu, Shu, Deng, Hongyu, Li, Dong, Gao, Pu
• Format: Article
• Language: English
• Subjects: cGAS; cGAS-STING pathway; herpesvirus; host-pathogen interaction; ORF52; ORF9; phase separation; VP22
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.05.002

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. [Display omitted] •ORF52/VP22-type viral proteins restrict cGAS-DNA condensates in vitro and in cells•Restriction process is dependent on DNA-induced phase separation of viral proteins•Virion-carried ORF52 can target cGAS-DNA condensates in early infection stage•Restriction of cGAS-DNA condensates represents a new viral immune evasion strategy cGAS-DNA phase separation is essential for the antiviral innate immune response. Xu et al. identify an evolutionarily divergent, but structurally related, viral tegument protein family that employs an interesting and conserved mechanism to restrict cGAS-DNA phase separation.