MicroRNA-200c-targeted contactin 1 facilitates the replication of influenza A virus by accelerating the degradation of MAVS.
MicroRNA-200c-targeted contactin 1 facilitates the replication of influenza A virus by accelerating the degradation of MAVS.
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MicroRNA-200c 靶向的 contactin 1 通过加速 MAVS 的降解来促进甲型流感病毒的复制。
DOI：
10.1371/journal.ppat.1010299
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发表时间：
2022-03
期刊：
影响因子：
6.7
通讯作者：
Zhu Q
中科院分区：
文献类型：
--
作者：
Xu S;Han L;Wei Y;Zhang B;Wang Q;Liu J;Liu M;Chen Z;Wang Z;Chen H;Zhu Q
甲型流感病毒（IAV）持续挑战家禽业和人类健康。阐明调节IAV生命周期的宿主因子对于开发抗病毒药物和疫苗至关重要。在这项研究中，我们用IAV感染A549细胞，发现宿主蛋白接触蛋白1（CNTN 1），免疫球蛋白超家族的成员，增强病毒复制。生物信息学预测和实验验证表明microRNA-200 c（miR-200 c）通过直接靶向作用降低CNTN 1的表达。我们进一步表明CNTN 1调节的A549细胞中的病毒复制依赖于I型干扰素信号传导。免疫共沉淀实验表明，CNTN 1特异性地与MAVS相互作用，并通过去除其K63连接的泛素化来促进其蛋白酶体降解。此外，我们发现去泛素化酶USP 25被CNTN 1募集以催化K63连接的MAVS的去泛素化。因此，CNTN 1诱导的MAVS降解级联阻断了RIG-I-MAVS介导的干扰素信号传导，导致病毒复制增强。总之，我们的数据揭示了CNTN 1在I型干扰素途径和IAV复制调节机制中的新作用。I型干扰素是宿主抵抗甲型流感病毒感染的免疫力的重要组成部分。然而，参与IAV诱导的I型干扰素途径的调节机制尚未完全阐明。在这里，我们确定CNTN 1作为一个关键的主机因子的复制IAV。CNTN 1通过负调节RIG-I介导的I型干扰素途径促进病毒复制。CNTN 1通过促进USP 25介导的去泛素化，特异性增强MAVS的蛋白酶体降解。我们的研究结果揭示了宿主蛋白CNTN 1在I型干扰素信号传导和IAV复制中的新作用。
Influenza A viruses (IAVs) continuously challenge the poultry industry and human health. Elucidation of the host factors that modulate the IAV lifecycle is vital for developing antiviral drugs and vaccines. In this study, we infected A549 cells with IAVs and found that host protein contactin-1 (CNTN1), a member of the immunoglobulin superfamily, enhanced viral replication. Bioinformatic prediction and experimental validation indicated that the expression of CNTN1 was reduced by microRNA-200c (miR-200c) through directly targeting. We further showed that CNTN1-modulated viral replication in A549 cells is dependent on type I interferon signaling. Co-immunoprecipitation experiments revealed that CNTN1 specifically interacts with MAVS and promotes its proteasomal degradation by removing its K63-linked ubiquitination. Moreover, we discovered that the deubiquitinase USP25 is recruited by CNTN1 to catalyze the deubiquitination of K63-linked MAVS. Consequently, the CNTN1-induced degradation cascade of MAVS blocked RIG-I-MAVS-mediated interferon signaling, leading to enhanced viral replication. Taken together, our data reveal novel roles of CNTN1 in the type I interferon pathway and regulatory mechanism of IAV replication. Type I interferon is an essential component of host immunity against influenza A virus infection. However, the regulatory mechanisms involved in the IAV-induced type I interferon pathway are not fully elucidated. Here, we identified CNTN1 as a critical host factor for the replication of IAV. CNTN1 promotes viral replication by negatively regulating the RIG-I-mediated type I interferon pathway. Mechanistically, CNTN1 specifically enhances the proteasomal degradation of MAVS by promoting USP25-mediated deubiquitination. Our findings uncover novel roles of the host protein CNTN1 in type I interferon signaling and IAV replication.
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