The Ca2+-dependent phosphatase calcineurin dephosphorylates TBK1 to suppress antiviral innate immunity

文献类型： 外文期刊

第一作者： Qu, Yang

作者： Qu, Yang;Yang, Zengqi;Qu, Yang;Wang, Siyuan;Jiang, Hui;Wang, Qingyi;Liao, Ying;Qiu, Xusheng;Tan, Lei;Song, Cuiping;Ding, Chan;Sun, Yingjie;Wang, Siyuan;Wang, Qingyi;Ding, Chan

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关键词： Ca2+; virus infection; calcineurin; TBK1; antiviral immunity

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：5.4； 五年影响因子：4.9 ）

ISSN： 0022-538X

年卷期： 2024 年 98 卷 5 期

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收录情况： SCI

摘要： Tumor necrosis factor receptor-associated factor family member-associated NF-kappa B activator-binding kinase 1 (TBK1) plays a key role in the induction of the type 1 interferon (IFN-I) response, which is an important component of innate antiviral defense. Viruses target calcium (Ca2+) signaling networks, which participate in the regulation of the viral life cycle, as well as mediate the host antiviral response. Although many studies have focused on the role of Ca2+ signaling in the regulation of IFN-I, the relationship between Ca2+ and TBK1 in different infection models requires further elucidation. Here, we examined the effects of the Newcastle disease virus (NDV)-induced increase in intracellular Ca2+ levels on the suppression of host antiviral responses. We demonstrated that intracellular Ca2+ increased significantly during NDV infection, leading to impaired IFN-I production and antiviral immunity through the activation of calcineurin (CaN). Depletion of Ca-2(+) was found to lead to a significant increase in virus-induced IFN-I production resulting in the inhibition of viral replication. Mechanistically, the accumulation of Ca2+ in response to viral infection increases the phosphatase activity of CaN, which in turn dephosphorylates and inactivates TBK1 in a Ca2+-dependent manner. Furthermore, the inhibition of CaN on viral replication was counteracted in TBK1 knockout cells. Together, our data demonstrate that NDV hijacks Ca2+ signaling networks to negatively regulate innate immunity via the CaN-TBK1 signaling axis. Thus, our findings not only identify the mechanism by which viruses exploit Ca2+ signaling to evade the host antiviral response but also, more importantly, highlight the potential role of Ca2+ homeostasis in the viral innate immune response.

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