Génin Pierre, Cuvelier Frédérique, Lambin Sandrine, Côrte-Real Filipe Josina, Autrusseau Elodie, Laurent Christine, Laplantine Emmanuel, Weil Robert
Laboratoire de Signalisation et Pathogenèse, CNRS UMR3691, Institut Pasteur, Paris, France.
Plate-Forme Protéomique, Institut Pasteur, Paris, France.
PLoS Pathog. 2015 Apr 29;11(4):e1004877. doi: 10.1371/journal.ppat.1004877. eCollection 2015 Apr.
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.
病毒入侵宿主最初由先天免疫系统识别，主要通过激活细胞内胞质信号通路以及协同激活促进I型干扰素基因诱导的干扰素调节因子3（IRF3）和核因子κB（NF-κB）转录因子来实现。TANK结合激酶1（TBK1）使IRF3磷酸化并激活它。在此，我们表明，Optineurin（Optn）通过将去泛素化酶CYLD靶向TBK1来抑制其酶活性，从而减弱抗病毒先天免疫反应。重要的是，我们发现由于CYLD和Optn的核转位，这种调节机制在G2/M期被消除。因此，我们观察到，在这个细胞分裂阶段，TBK1的活性和磷酸化增加，导致其重新定位于线粒体并增强干扰素产生，这表明这个依赖于Optn功能的过程，可能对于在有丝分裂期间发起预防性抗病毒反应至关重要。
