Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.
Cell Host Microbe. 2012 Aug 16;12(2):211-22. doi: 10.1016/j.chom.2012.06.009.
The RIG-I/Mda5 sensors recognize viral intracellular RNA and trigger host antiviral responses. RIG-I signals through the adaptor protein MAVS, which engages various TRAF family members and results in type I interferon (IFNs) and proinflammatory cytokine production via activation of IRFs and NF-κB, respectively. Both the IRF and NF-κB pathways also require the adaptor protein NEMO. We determined that the RIG-I pathway is differentially regulated by the linear ubiquitin assembly complex (LUBAC), which consists of the E3 ligases HOIL-1L, HOIP, and the accessory protein SHARPIN. LUBAC downregulated virus-mediated IFN induction by targeting NEMO for linear ubiquitination. Linear ubiquitinated NEMO associated with TRAF3 and disrupted the MAVS-TRAF3 complex, which inhibited IFN activation while stimulating NF-κB-dependent signaling. In SHARPIN-deficient MEFs, vesicular stomatitis virus replication was decreased due to increased IFN production. Linear ubiquitination thus switches NEMO from a positive to a negative regulator of RIG-I signaling, resulting in an attenuated IFN response.
RIG-I/Mda5 传感器识别病毒细胞内 RNA 并触发宿主抗病毒反应。RIG-I 通过衔接蛋白 MAVS 发出信号，该蛋白与各种 TRAF 家族成员结合，分别通过激活 IRFs 和 NF-κB 导致 I 型干扰素 (IFNs) 和促炎细胞因子的产生。IRF 和 NF-κB 途径还需要衔接蛋白 NEMO。我们确定 RIG-I 途径受到线性泛素组装复合物 (LUBAC) 的差异调节，该复合物由 E3 连接酶 HOIL-1L、HOIP 和辅助蛋白 SHARPIN 组成。LUBAC 通过针对 NEMO 的线性泛素化来下调病毒介导的 IFN 诱导。线性泛素化的 NEMO 与 TRAF3 相关联，并破坏了 MAVS-TRAF3 复合物，这抑制了 IFN 激活，同时刺激了 NF-κB 依赖性信号传导。在 SHARPIN 缺陷型 MEFs 中，由于 IFN 产生增加，水疱性口炎病毒复制减少。因此，线性泛素化将 NEMO 从 RIG-I 信号的正调控因子转变为负调控因子，导致 IFN 反应减弱。
