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Functional regulation of MyD88-activated interferon regulatory factor 5 by K63-linked polyubiquitination.

Interferon regulatory factor 5 (IRF-5) plays an important role in the innate antiviral and inflammatory response. Specific IRF-5 haplotypes are associated with dysregulated expression of type I interferons and predisposition to autoimmune disorders. IRF-5 is activated by Toll-like receptor 7 (TLR7) and TLR9 via the MyD88 pathway, where it interacts with both MyD88 and the E3 ubiquitin ligase, TRAF6. To understand the role of these interactions in the regulation of IRF-5, we examined the role of ubiquitination and showed that IRF-5 is subjected to TRAF6-mediated K63-linked ubiquitination, which is important for IRF-5 nuclear translocation and target gene regulation. We show that while the murine IRF-5 and human IRF-5 variant 4 (HuIRF-5v4) and HuIRF-5v5 are ubiquitinated, an IRF-5 bone marrow variant mutant containing an internal deletion of 288 nucleotides is not ubiquitinated. Lysine residues at positions 410 and 411 in a putative TRAF6 consensus binding domain of IRF-5 are the targets of K63-linked ubiquitination. Mutagenesis of these two lysines abolished IRF-5 ubiquitination, nuclear translocation, and the IFNA promoter-inducing activity but not the IRF-5-TRAF6 interaction. Finally, we show that IRAK1 associates with IRF-5 and that this interaction precedes and is required for IRF-5 ubiquitination and activation. Thus, our findings offer a new mechanistic insight into IRF-5 gene induction program through hitherto unknown processes of IRF-5 ubiquitination.

Pubmed ID: 18824541

Authors

  • Balkhi MY
  • Fitzgerald KA
  • Pitha PM

Journal

Molecular and cellular biology

Publication Data

December 25, 2008

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI067497
  • Agency: NCI NIH HHS, Id: CA19737-22A1
  • Agency: NIAID NIH HHS, Id: R01 AI067632-02A1

Mesh Terms

  • Animals
  • Cell Line
  • Cell Nucleus
  • Humans
  • Interferon Regulatory Factors
  • Interferon Type I
  • Interleukin-1 Receptor-Associated Kinases
  • Lysine
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88
  • Polyubiquitin
  • Signal Transduction
  • TNF Receptor-Associated Factor 6
  • Ubiquitination