Human metapneumovirus M2-2 protein inhibits RIG-I signaling by preventing TRIM25-mediated RIG-I ubiquitination.
Human metapneumovirus M2-2 protein inhibits RIG-I signaling by preventing TRIM25-mediated RIG-I ubiquitination.
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DOI：
10.3389/fimmu.2022.970750
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
视黄酸诱导基因I（RIG-I）是感测病毒RNA并与线粒体抗病毒信号传导（MAVS）蛋白相互作用的受体，导致I型干扰素和炎性细胞因子的产生以建立抗病毒状态。该信号传导轴由K63连接的RIG-I泛素化启动，由E3泛素连接酶如TRIM 25介导。然而，许多病毒，包括副粘病毒科的几个成员和人呼吸道合胞病毒（HRSV）（肺病毒科的一个成员），通过靶向RIG-I/TRIM 25信号传导逃避免疫系统。在这项研究中，我们筛选了人偏肺病毒（HMPV）开放阅读框（ORF），以确定其阻断RIG-I信号转导的能力，该信号转导是通过转染TRIM 25和RIG-I CARD（一种在RIG-I信号转导中具有组成性活性的N-末端CARD结构域）在HEK 293 T细胞中重建的。HMPV M2-2是RIG-I/TRIM 25介导的干扰素（IFN）-β激活的最有效抑制剂。M2-2沉默诱导A549细胞中RIG-I信号传导下游的转录因子（IRF和NF-kB）的激活。此外，M2-2抑制RIG-I泛素化和CARD依赖性与MAVS的相互作用。免疫沉淀显示M2-2通过与TRIM 25的SPRY结构域直接相互作用与RIG-I CARD/TRIM 25形成稳定的复合物。同样，HRSV NS 1也与RIG-I CARD/TRIM 25形成稳定的复合物，并抑制RIG-I泛素化。值得注意的是，HMPV M2-2和HRSV NS 1的抑制作用与副粘病毒科几个成员的V蛋白的抑制作用相似。在这项研究中，我们已经确定了一种新的机制，免疫逃逸HMPV，类似于肺炎病毒科和副粘病毒科的家庭成员。
Retinoic acid-inducible gene I (RIG-I) is a receptor that senses viral RNA and interacts with mitochondrial antiviral signaling (MAVS) protein, leading to the production of type I interferons and inflammatory cytokines to establish an antiviral state. This signaling axis is initiated by the K63-linked RIG-I ubiquitination, mediated by E3 ubiquitin ligases such as TRIM25. However, many viruses, including several members of the family Paramyxoviridae and human respiratory syncytial virus (HRSV), a member of the family Pneumoviridae, escape the immune system by targeting RIG-I/TRIM25 signaling. In this study, we screened human metapneumovirus (HMPV) open reading frames (ORFs) for their ability to block RIG-I signaling reconstituted in HEK293T cells by transfection with TRIM25 and RIG-I CARD (an N-terminal CARD domain that is constitutively active in RIG-I signaling). HMPV M2-2 was the most potent inhibitor of RIG-I/TRIM25-mediated interferon (IFN)-β activation. M2-2 silencing induced the activation of transcription factors (IRF and NF-kB) downstream of RIG-I signaling in A549 cells. Moreover, M2-2 inhibited RIG-I ubiquitination and CARD-dependent interactions with MAVS. Immunoprecipitation revealed that M2-2 forms a stable complex with RIG-I CARD/TRIM25 via direct interaction with the SPRY domain of TRIM25. Similarly, HRSV NS1 also formed a stable complex with RIG-I CARD/TRIM25 and inhibited RIG-I ubiquitination. Notably, the inhibitory actions of HMPV M2-2 and HRSV NS1 are similar to those of V proteins of several members of the Paramyxoviridae family. In this study, we have identified a novel mechanism of immune escape by HMPV, similar to that of Pneumoviridae and Paramyxoviridae family members.
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