MCB Accepts, published online ahead of print on 12 February 2007

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Mol. Cell. Biol. doi:10.1128/MCB.02256-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

IRF7 is activated by a viral oncoprotein through RIP-dependent Ubiquitination

Leslie E. Huye, Shunbin Ning, Michelle Kelliher, and Joseph S. Pagano^*

Department of Medicine, Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, MA 01605

^* To whom correspondence should be addressed. Email: joseph_pagano{at}med.unc.edu.

As a key mediator of type-I interferon (IFN-/) responses, Interferon Regulatory Factor (IRF) 7 is essential to host immune defenses. Activation of IRF7 generally requires virus-induced C-terminal phosphorylation, which leads to its nuclear accumulation and activation of target genes. Here we use the EBV oncoprotein, LMP1, which activates IRF7, to identify factors involved in IRF7 activation. We demonstrate for the first time that RIP activates IRF7 and that RIP and IRF7 interact under physiological conditions in EBV-positive Burkitt's lymphoma cells. We provide evidence that both RIP and IRF7 are ubiquitinated in these cells and that IRF7 preferentially interacts with ubiquitinated RIP. RIP is required for full activation of IRF7 by LMP1, with LMP1 stimulating the ubiquitination of RIP and its interaction with IRF7. Moreover, LMP1 stimulates RIP-dependent K63-linked ubiquitination of IRF7, which regulates protein function rather than proteasomal degradation of proteins. We suggest that RIP may serve as a general activator of IRF7, responding to and transmitting the signal from various stimuli, and that ubiquitination may be a general mechanism for enhancing the activity of IRF7.

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