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Molecular and Cellular Biology, December 2008, p. 7296-7308, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00662-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Functional Regulation of MyD88-Activated Interferon Regulatory Factor 5 by K63-Linked Polyubiquitination {triangledown}

Mumtaz Yaseen Balkhi,1 Katherine A. Fitzgerald,4 and Paula M. Pitha1,2,3*

Sidney Kimmel Comprehensive Cancer Center,1 Department of Molecular Biology and Genetics,2 Biology Department, Johns Hopkins University, Baltimore, Maryland 21231,3 Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 016054

Received 23 April 2008/ Returned for modification 21 May 2008/ Accepted 22 September 2008

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.

* Corresponding author. Mailing address: Johns Hopkins School of Medicine, 1650 Orleans St., Baltimore, MD 21231. Phone: (410) 955-8871. Fax: (410) 955-0840. E-mail: parowe{at}jhmi.edu

{triangledown} Published ahead of print on 29 September 2008.

Molecular and Cellular Biology, December 2008, p. 7296-7308, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00662-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wies, E., Hahn, A. S., Schmidt, K., Viebahn, C., Rohland, N., Lux, A., Schellhorn, T., Holzer, A., Jung, J. U., Neipel, F. (2009). The Kaposi's Sarcoma-associated Herpesvirus-encoded vIRF-3 Inhibits Cellular IRF-5. J. Biol. Chem. 284: 8525-8538 [Abstract] [Full Text]  


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