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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Amino Acid Substitution
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Cell Cycle Proteins
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Cell Line
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Deubiquitinating Enzyme CYLD
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G2 Phase
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Genes, Reporter
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Humans
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Immunity, Innate*
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Interferon-beta / genetics
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Interferon-beta / metabolism*
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Membrane Transport Proteins
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Mitosis*
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Mutation
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein Transport
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RNA Interference
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RNA, Small Interfering
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Transcription Factor TFIIIA / antagonists & inhibitors
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Transcription Factor TFIIIA / genetics
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Transcription Factor TFIIIA / metabolism*
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Tumor Suppressor Proteins / agonists
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Up-Regulation*
Substances
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Cell Cycle Proteins
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Membrane Transport Proteins
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OPTN protein, human
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RNA, Small Interfering
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Recombinant Proteins
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Transcription Factor TFIIIA
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Tumor Suppressor Proteins
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Interferon-beta
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Protein Serine-Threonine Kinases
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TBK1 protein, human
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CYLD protein, human
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Deubiquitinating Enzyme CYLD
Grants and funding
PG, EL and RW were supported by CNRS. JCRF was a recipient of the Fundação para a Ciência e Tecnologia fellowship. Work in the laboratory of RW is supported by l’Institut National du Cancer (INCa) and by the Association pour la Recherche sur le Cancer (ARC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.