HIV-1 Vif suppresses antiviral immunity by targeting STING
HIV-1 Vif suppresses antiviral immunity by targeting STING
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HIV-1 Vif 通过靶向 STING 抑制抗病毒免疫
DOI：
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发表时间：
2021
影响因子：
24.1
通讯作者：
Dapeng Yan
中科院分区：
文献类型：
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作者：
Yu Wang;G. Qian;Lingyan Zhu;Zhuo Zhao;Yi;Wendong Han;Xiaokai Zhang;Yihua Zhang;Tingrong Xiong;H. Zeng;Xianghui Yu;Xiaofang Yu;Xiaoyan Zhang;Jianqing Xu;Q. Zou;Dapeng Yan
HIV-1感染诱导的cGAS-STING-TBK1-IRF3信号激活先天免疫产生I型干扰素。HIV-1非结构蛋白病毒感染性因子(Vif)在HIV-1复制过程中是必不可少的，因为它能降解宿主限制因子APOBEC3G。然而，它是否以及如何调节宿主的免疫反应仍有待确定。在这项研究中，我们发现Vif抑制I型干扰素的产生，以促进免疫逃避。HIV-1感染诱导宿主酪氨酸激酶Frk激活，进而磷酸化Vif的免疫受体酪氨酸抑制基序(ITIM)，增强Vif与细胞酪氨酸磷酸酶SHP-1的相互作用，从而抑制I型干扰素。从机制上讲，Vif与SHP-1的结合促进了SHP-1对STING的招募，并通过使Tyr162上的STING去磷酸化而抑制了Lys337上K63连锁的STING泛素化。而FRK抑制剂D-65495则可阻断Vif的磷酸化，从而阻断HIV-1的免疫逃避和抗感染。这些发现揭示了一种先前未知的机制，即HIV-1通过含有ITIM的蛋白来抑制STING的翻译后修饰来逃避抗病毒免疫。这些结果为开发治疗HIV-1感染的新治疗策略提供了分子基础。
HIV-1 infection-induced cGAS–STING–TBK1–IRF3 signaling activates innate immunity to produce type I interferon (IFN). The HIV-1 nonstructural protein viral infectivity factor (Vif) is essential in HIV-1 replication, as it degrades the host restriction factor APOBEC3G. However, whether and how it regulates the host immune response remains to be determined. In this study, we found that Vif inhibited the production of type I IFN to promote immune evasion. HIV-1 infection induced the activation of the host tyrosine kinase FRK, which subsequently phosphorylated the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Vif and enhanced the interaction between Vif and the cellular tyrosine phosphatase SHP-1 to inhibit type I IFN. Mechanistically, the association of Vif with SHP-1 facilitated SHP-1 recruitment to STING and inhibited the K63-linked ubiquitination of STING at Lys337 by dephosphorylating STING at Tyr162. However, the FRK inhibitor D-65495 counteracted the phosphorylation of Vif to block the immune evasion of HIV-1 and antagonize infection. These findings reveal a previously unknown mechanism through which HIV-1 evades antiviral immunity via the ITIM-containing protein to inhibit the posttranslational modification of STING. These results provide a molecular basis for the development of new therapeutic strategies to treat HIV-1 infection.
影响因子：
30.5
作者：
Herzner AM;Hagmann CA;Goldeck M;Wolter S;Kübler K;Wittmann S;Gramberg T;Andreeva L;Hopfner KP;Mertens C;Zillinger T;Jin T;Xiao TS;Bartok E;Coch C;Ackermann D;Hornung V;Ludwig J;Barchet W;Hartmann G;Schlee M
通讯作者：
Schlee M
影响因子：
30.3
作者：
Hotter, Dominik;Bosso, Matteo;Kirchhoff, Frank
通讯作者：
Kirchhoff, Frank
影响因子：
30.3
作者：
Luban J
通讯作者：
Luban J