PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection.
PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection.
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PCV2靶向cGAS抑制I型干扰素诱导促进其他DNA病毒感染
DOI：
10.1371/journal.ppat.1009940
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发表时间：
2021-09
期刊：
影响因子：
6.7
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Wang Z;Chen J;Wu X;Ma D;Zhang X;Li R;Han C;Liu H;Yin X;Du Q;Tong D;Huang Y
病毒通过多种策略损害宿主的抗病毒免疫力，促进感染和致病。在此，我们发现PCV 2感染通过抑制IFN-β的诱导作用促进DNA病毒的感染。在感染的早期阶段，PCV 2通过激活PI 3 K/Akt信号传导促进cGAS在S278处的磷酸化，这直接沉默cGAS的催化活性。随后，cGAS在S278处的磷酸化可以促进cGAS在K389处的K48-连接的多聚泛素化，其可以用作被组蛋白脱乙酰酶6（HDAC 6）的泛素结合结构域识别的信号，以促进K48-泛素化的cGAS根据HDAC 6的脱乙酰酶活性从胞质溶胶易位到自溶小体，从而最终导致相对于Earle平衡盐溶液（EBSS）诱导的自噬细胞（典型的饥饿自噬），PCV 2感染诱导的自噬细胞中CGAS降解显著增加。重要的是，我们发现PCV 2 Cap及其结合蛋白gC 1 qR作为主要调节剂，通过介导PI 3 K/AKT信号传导和PKCδ信号传导激活来促进猪cGAS磷酸化和HDAC 6激活。基于这一发现，与野生型PCV 2相比，gC 1 qR结合活性缺陷型PCV 2突变体（PCV 2 RmA）确实显示出对IFN-β诱导的抑制作用减弱，对其他DNA病毒感染的加强作用减弱。总的来说，我们的研究结果阐明了猪圆环病毒抵消cGAS-STING信号通路以抑制I型干扰素诱导并促进DNA病毒感染的系统调节机制，并确定gC 1 qR是PCV 2诱导的免疫抑制的重要调节剂。
Viruses use diverse strategies to impair the antiviral immunity of host in order to promote infection and pathogenesis. Herein, we found that PCV2 infection promotes the infection of DNA viruses through inhibiting IFN-β inductionin vivoandin vitro. In the early phase of infection, PCV2 promotes the phosphorylation of cGAS at S278 via activation of PI3K/Akt signaling, which directly silences the catalytic activity of cGAS. Subsequently, phosphorylation of cGAS at S278 can facilitate the K48-linked poly-ubiquitination of cGAS at K389, which can been served as a signal for recognizing by the ubiquitin-binding domain of histone deacetylase 6 (HDAC6), to promote the translocation of K48-ubiquitinated-cGAS from cytosol to autolysosome depending on the deacetylase activity of HDAC6, thereby eventually resulting in a markedly increased cGAS degradation in PCV2 infection-induced autophagic cells relative to Earle’s Balanced Salt Solution (EBSS)-induced autophagic cells (a typical starving autophagy). Importantly, we found that PCV2 Cap and its binding protein gC1qR act as predominant regulators to promote porcine cGAS phosphorylation and HDAC6 activation through mediating PI3K/AKT signaling and PKCδ signaling activation. Based on this finding, gC1qR-binding activity deficient PCV2 mutant (PCV2RmA) indeed shows a weakened inhibitory effect on IFN-β induction and a weaker boost effect for other DNA viruses infection compared to wild-type PCV2. Collectively, our findings illuminate a systematic regulation mechanism by which porcine circovirus counteracts the cGAS-STING signaling pathway to inhibit the type I interferon induction and promote DNA virus infection, and identify gC1qR as an important regulator for the immunosuppression induced by PCV2.
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