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OTUD1 Negatively Regulates Type I IFN Induction by Disrupting Noncanonical Ubiquitination of IRF3

The Journal of immunology (1950), 2020-04, Vol.204 (7), p.1904-1918 [Peer Reviewed Journal]

Copyright © 2020 by The American Association of Immunologists, Inc. ;ISSN: 0022-1767 ;EISSN: 1550-6606 ;DOI: 10.4049/jimmunol.1900305 ;PMID: 32075857

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  • Title:
    OTUD1 Negatively Regulates Type I IFN Induction by Disrupting Noncanonical Ubiquitination of IRF3
  • Author: Zhang, Zeming ; Wang, Dandan ; Wang, Peiyan ; Zhao, Yingchi ; You, Fuping
  • Is Part Of: The Journal of immunology (1950), 2020-04, Vol.204 (7), p.1904-1918
  • Description: IFN regulatory factor 3 (IRF3) is critical for the transcription of type I IFNs in defensing virus and promoting inflammatory responses. Although several kinds of posttranslational modifications have been identified to modulate the activity of IRF3, whether atypical ubiquitination participates in the function regulation, especially the DNA binding capacity of IRF3, is unknown. In this study, we found that the ovarian tumor domain containing deubiquitinase OTUD1 deubiquitinated IRF3 and attenuated its function. An atypical ubiquitination, K6-linked ubiquitination, was essential for the DNA binding capacity of IRF3 and subsequent induction of target genes. Mechanistically, OTUD1 cleaves the viral infection-induced K6-linked ubiquitination of IRF3, resulting in the disassociation of IRF3 from the promoter region of target genes, without affecting the protein stability, dimerization, and nuclear translocation of IRF3 after a viral infection. cells as well as mice produced more type I IFNs and proinflammatory cytokines after viral infection. mice were more resistant to lethal HSV-1 and VSV infection. Consistent with the former investigations that IRF3 promoted inflammatory responses in LPS-induced sepsis, mice were more susceptible to LPS stimulation. Taken together, our findings revealed that the DNA binding capacity of IRF3 in the innate immune signaling pathway was modulated by atypical K6-linked ubiquitination and deubiquitination process, which was regulated by the deubiquitinase OTUD1.
  • Publisher: United States
  • Language: English
  • Identifier: ISSN: 0022-1767
    EISSN: 1550-6606
    DOI: 10.4049/jimmunol.1900305
    PMID: 32075857
  • Source: Geneva Foundation Free Medical Journals at publisher websites
    Alma/SFX Local Collection
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