Mitochondrial DUT-M potentiates RLR-mediated antiviral signaling by enhancing VISA and TRAF2 association.

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  • Additional Information
    • Source:
      Publisher: Pergamon Press Country of Publication: England NLM ID: 7905289 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-9142 (Electronic) Linking ISSN: 01615890 NLM ISO Abbreviation: Mol Immunol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Oxford, Elmsford, N. Y., Pergamon Press.
    • Subject Terms:
      Adaptor Proteins, Signal Transducing/*metabolism ; Antiviral Agents/*metabolism ; Mitochondria/*metabolism ; Pyrophosphatases/*metabolism ; Signal Transduction/*physiology ; TNF Receptor-Associated Factor 2/*metabolism; HEK293 Cells ; Humans ; Immunity, Innate/physiology ; Interferon Regulatory Factor-3/metabolism ; Phosphorylation/physiology ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination/physiology
    • Abstract:
      Upon recognition of intracytoplasmic viral RNA, activated RIG-I is recruited to the mitochondrion-located adaptor protein VISA (also known as MAVS, CARDIF, and IPS-1). VISA then acts as a central signaling platform for linking RIG-I and downstream signaling components, such as TRAF2, 5, and 6, TBK1, and IKK, leading to activation of the kinases TBK1 and IKK. These activated kinases further phosphorylate the transcription factors IRF3/7 and NF-κB, leading to the induction of downstream antiviral genes. Here, we report a mitochondrial isoform, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), DUT-M, as a positive regulator in RLR-VISA-mediated antiviral signaling. DUT-M interacts with VISA and RIG-I to facilitate the assembly of the VISA-TRAF2 complex and to augment the polyubiquitination of TRAF2, leading to potentiated activation of IRF3 dimerization and phosphorylation of P65, and enhanced VISA-mediated innate immune response. RLR-VISA-mediated IRF3 dimerization and P65 phosphorylation, were inhibited in DUT-knockdown and DUT-deficient 293 cells. Thus, DUT-M is a positive regulator of the RIG-I-VISA-mediated innate immune response to RNA viruses.
      (Copyright © 2021 Elsevier Ltd. All rights reserved.)
    • Contributed Indexing:
      Keywords: DUT-M; RLR signaling; TRAF2; VISA
    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (Antiviral Agents)
      0 (Interferon Regulatory Factor-3)
      0 (MAVS protein, human)
      0 (PSMD2 protein, human)
      0 (TNF Receptor-Associated Factor 2)
      EC 2.3.2.27 (Ubiquitin-Protein Ligases)
      EC 3.6.1.- (Pyrophosphatases)
      EC 3.6.1.- (uridine triphosphatase)
    • Publication Date:
      Date Created: 20210214 Date Completed: 20210423 Latest Revision: 20210423
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/j.molimm.2021.01.023
    • Accession Number:
      33582548