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

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 inter-feron 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) phos-phorylates 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 phosphoryla-tion 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. The innate immune system has evolved to detect and neutralize viral invasion. Triggering of this defense mechanism relies on the production and secretion of soluble factors that stimulate an intracellular antiviral defense mechanism. The protein Optineurin was shown to negatively regulate this process. Importantly, we discovered the mechanism by which Optineurin inhibits antiviral activity and showed that this regulation is prevented during a critical step of cell division leading to enhancement of the cellular defense mechanism. This paper shows that the antiviral immune system is controlled during the cell cycle and that Optineurin-mediated induction of this system might serve to protect cells from infection during cell division.
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Submitted on : Thursday, April 30, 2015 - 11:43:39 AM
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Pierre Génin, Frédérique Cuvelier, Sandrine Lambin, Josina Côrte-Real, Elodie Autrusseau, et al.. Optineurin Regulates the Interferon Response in a Cell Cycle-Dependent Manner. PLoS Pathogens, Public Library of Science, 2015, 11 (4), pp.e1004877. ⟨10.1371/journal.ppat.1004877⟩. ⟨pasteur-01147388⟩

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