Optineurin Regulates the Interferon Response in a Cell Cycle-Dependent Manner

Viral invasion into a host is initially recognized by the innate immune system, mainly through activation of the intracellular cytosolic signaling pathway and coordinated activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB) transcription factors that promote type I interferon gene induction. The TANK-binding Kinase 1 (TBK1) phosphorylates and activates IRF3. Here, we show that Optineurin (Optn) dampens the antiviral innate immune response by targeting the deubiquitinating enzyme CYLD to TBK1 in order to inhibit its enzymatic activity. Importantly, we found that this regulatory mechanism is abolished at the G2/M phase as a consequence of the nuclear translocation of CYLD and Optn. As a result, we observed, at this cell division stage, an increased activity and phosphorylation of TBK1 that lead to its relocalization to mitochondria and to enhanced interferon production, suggesting that this process, which relies on Optn function, might be of major importance to mount a preventive antiviral response during mitosis.

病毒入侵宿主初始会被先天免疫系统识别，该识别过程主要通过激活胞内胞质信号通路，协同促进干扰素调节因子3（interferon regulatory factor 3, IRF3）与核因子κB（nuclear factor kappa B, NF-κB）转录因子的活化，进而诱导I型干扰素的基因表达。TANK结合激酶1（TANK-binding Kinase 1, TBK1）可通过磷酸化修饰激活IRF3。本研究显示，视神经蛋白（Optineurin, Optn）可将去泛素化酶CYLD靶向募集至TBK1，通过抑制其酶活性负调控抗病毒先天免疫应答。重要的是，该调控机制在G2/M期会因CYLD与Optn发生核转位而被解除。在此细胞分裂阶段，我们观察到TBK1的酶活性与磷酸化水平均升高，使其向线粒体发生重新定位，并伴随干扰素生成增强；这表明依赖Optn功能的该过程，或许对细胞在有丝分裂期间启动预防性抗病毒应答具有关键意义。