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WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines

Kun Zhu1, Xiang Wang1, Lin-Gao Ju1

  • 1Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.

Journal of Immunology (Baltimore, Md. : 1950)
|November 1, 2015
PubMed

Insights

WD repeat domain 82 (WDR82) acts as a negative regulator in the host

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are crucial for recognizing viral RNA and initiating type I interferon (IFN) responses.
  • WD repeat domain 5 (WDR5) was previously identified as a positive regulator of the RIG-I signaling pathway.
  • The role of WDR82, a WDR5 homolog, in antiviral immunity remained largely uncharacterized.

Purpose of the Study:

  • To investigate the function of WDR82 in the context of virus-triggered type I IFN production.
  • To elucidate the molecular mechanism by which WDR82 regulates the RIG-I signaling pathway.

Main Methods:

  • Overexpression and knockdown of WDR82 in host cells.
  • Analysis of type I IFN expression (e.g., IFN-β, IFNB1) upon viral infection.
  • Mitochondrial localization studies using WDR82 mutants.
  • Co-immunoprecipitation assays to study protein interactions.
  • Western blotting to assess polyubiquitination status of TRAF3.
  • Viral replication assays.

Main Results:

  • WDR82 functions as a negative regulator, inhibiting RIG-I pathway activation and type I IFN expression.
  • WDR82 overexpression suppressed virus-induced IFN-β, while WDR82 knockdown enhanced it.
  • WDR82 localizes to mitochondria, with its N-terminal WD40 domain being essential for this localization.
  • WDR82 interacts with TNFR-associated factor 3 (TRAF3) and promotes its K48-linked polyubiquitination, affecting its stability.
  • WDR82 knockdown inhibited viral replication, whereas overexpression promoted it.
  • WDR82's regulation of Sendai virus-induced IFNB1 expression is cell type-specific.

Conclusions:

  • WDR82 is a novel negative regulator of virus-triggered type I IFN production.
  • WDR82 mediates its inhibitory function by promoting TRAF3 polyubiquitination and affecting its stability on mitochondria.
  • WDR82 plays a significant role in controlling viral replication and innate antiviral responses.

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