The Zinc-Finger Protein ZCCHC3 Binds RNA and Facilitates Viral RNA Sensing and Activation of the RIG-I-like Receptors
The Zinc-Finger Protein ZCCHC3 Binds RNA and Facilitates Viral RNA Sensing and Activation of the RIG-I-like Receptors
复制标题
锌指蛋白 ZCCHC3 结合 RNA 并促进病毒 RNA 感应和 RIG-I 样受体的激活
DOI：
10.1016/j.immuni.2018.08.014
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发表时间：
2018-09-18
期刊：
影响因子：
32.4
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
--
作者：
Lian, Huan;Zang, Ru;Shu, Hong-Bing
视黄酸诱导基因I（RIG-I）样受体（RLR）识别病毒RNA启动先天性抗病毒免疫应答。病毒RNA与RLR的结合和RLR的激活是如何被调节的仍然是个谜。在这项研究中，我们确定ZCCHC3作为RIG-I和MDA 5等RLR的正调节因子。ZCCHC3缺陷显著抑制RNA病毒触发的下游抗病毒基因的诱导，ZCCHC3缺陷小鼠对RNA病毒感染更敏感。ZCCHC3与RIG-I和MDA 5相关，并在两个不同的过程中调节RIG-I和MDA 5活性。ZCCHC3与dsRNA结合，并增强RIG-I和MDA 5与dsRNA的结合。ZCCHC3还将E3泛素连接酶TRIM25募集到RIG-I和MDA 5复合物中，以促进其K63连接的多聚泛素化和活化。因此，ZCCHC3是RIG-I和MDA 5的共受体，其对于针对RNA病毒的TLR介导的先天免疫应答至关重要。
Recognition of viral RNA by the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiates innate antiviral immune response. How the binding of viral RNA to and activation of the RLRs are regulated remains enigmatic. In this study, we identified ZCCHC3 as a positive regulator of the RLRs including RIG-I and MDA5. ZCCHC3 deficiency markedly inhibited RNA virus-triggered induction of downstream antiviral genes, and ZCCHC3-deficient mice were more susceptible to RNA virus infection. ZCCHC3 was associated with RIG-I and MDA5 and functions in two distinct processes for regulation of RIG-I and MDA5 activities. ZCCHC3 bound to dsRNA and enhanced the binding of RIG-I and MDA5 to dsRNA. ZCCHC3 also recruited the E3 ubiquitin ligase TRIM25 to the RIG-I and MDA5 complexes to facilitate its K63-linked polyubiquitination and activation. Thus, ZCCHC3 is a co-receptor for RIG-I and MDA5, which is critical for RLR-mediated innate immune response to RNA virus.