A non-canonical role of the p97 complex in RIG-I antiviral signaling
A non-canonical role of the p97 complex in RIG-I antiviral signaling
复制标题
p97 复合物在 RIG-I 抗病毒信号传导中的非典型作用。
DOI：
10.15252/embj.201591888
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发表时间：
2015-12-02
期刊：
影响因子：
11.4
通讯作者：
Zhou, Zhaocai
中科院分区：
文献类型：
--
作者：
Hao, Qian;Jiao, Shi;Zhou, Zhaocai
RIG-I 是一种经过充分研究的病毒 RNA 传感器，在先天免疫中发挥着关键作用。 p97 调节多种细胞事件，如蛋白质质量控制、膜重组、DNA 修复和细胞周期。在这里，我们报道了 p97 以 Npl4-Ufd1 作为其辅因子，通过促进 RIG-I 的蛋白酶体降解来减少抗病毒先天免疫反应的新作用。 p97 复合物能够直接结合非泛素化的 RIG-I 和 E3 连接酶 RNF125，促进 RIG-I 在残基 K181 处的 K48 连接泛素化。病毒感染通过暴露 CARD 的 RIG-I 构象变化以及这些 CARD 的 K63 连接泛素化显着增强了 RIG-I 和 p97 复合物之间的相互作用。 p97 复合物的破坏增强了 RIG-I 抗病毒信号传导。一致地，施用针对 p97 ATP 酶活性的化合物可以抑制病毒复制并保护小鼠免受水泡性口炎病毒 (VSV) 感染。总体而言，我们的研究揭示了 p97 复合物在蛋白质泛素化中以前未被认识的作用，并揭示了 p97 复合物作为抗病毒治疗中的潜在药物靶点。
RIG-I is a well-studied sensor of viral RNA that plays a key role in innate immunity. p97 regulates a variety of cellular events such as protein quality control, membrane reassembly, DNA repair, and the cell cycle. Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. Viral infection significantly strengthens the interaction between RIG-I and the p97 complex by a conformational change of RIG-I that exposes the CARDs and through K63-linked ubiquitination of these CARDs. Disruption of the p97 complex enhances RIG-I antiviral signaling. Consistently, administration of compounds targeting p97 ATPase activity was shown to inhibit viral replication and protect mice from vesicular stomatitis virus (VSV) infection. Overall, our study uncovered a previously unrecognized role for the p97 complex in protein ubiquitination and revealed the p97 complex as a potential drug target in antiviral therapy.