Functional regulation of MyD88-activated interferon regulatory factor 5 by K63-linked polyubiquitination
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2008-10-01Keywords
AnimalsCell 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
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
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.Source
Mol Cell Biol. 2008 Dec;28(24):7296-308. Epub 2008 Sep 29. Link to article on publisher's siteDOI
10.1128/MCB.00662-08Permanent Link to this Item
http://hdl.handle.net/20.500.14038/35244PubMed ID
18824541Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1128/MCB.00662-08