Abstract
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.
Highlights
Innate immunity is a host mechanism found in most multicellular organisms that serves as a first line of defense against microbial pathogens
Optn acts as a negative regulator of the antiviral innate immune response To assess the role of Optn in antiviral host response, we used HeLa cell clones depleted of Optn using stably introduced shRNA, and stably complemented with either wild-type or mutated shRNA-resistant Optn plasmids that we previously generated to ensure a uniform ectopic expression equivalent to the endogenous level of Optn [38]
Since we have previously shown that Optn accumulates in the nucleus during the G2/M transition [38], we speculated that this Optn relocation could prevent Optn/CYLD-mediated inhibition of TANK-binding kinase-1 (TBK1) activity
Summary
Innate immunity is a host mechanism found in most multicellular organisms that serves as a first line of defense against microbial pathogens. Detection of pathogen associated molecular patterns (PAMPS) by the pattern-recognition receptors (PRR) activates intracellular signaling pathways that culminate in the production and secretion of pro-inflammatory cytokines, chemokines and type I IFN, i.e. IFN-α and IFN-β. Once secreted, these cytokines stimulate transcription of IFN-stimulated genes (ISGs), products of which prevent virus spreading and activate the adaptive immune responses [1,2]. These phosphorylations induce conformational changes in IRF3 that promote its dimerization, nuclear transport, and association with co-activators such as CBP/p300 and PCAF to stimulate their transcriptional activities [9,10]
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