Interferon regulatory factor 7 is activated by a viral oncoprotein through RIP-dependent ubiquitination.
As a key mediator of type I interferon (IFN) (IFN-alpha/beta) responses, IFN regulatory factor 7 (IRF7) 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 Epstein-Barr virus (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 signals from various stimuli, and that ubiquitination may be a general mechanism for enhancing the activity of IRF7.
Huye
Leslie E
LE
Lineberger Comprehensive Cancer Center, University of North Carolina, Campus Box 7295, Chapel Hill, NC 27599, USA.
Ning
Shunbin
S
Kelliher
Michelle
M
Pagano
Joseph S
JS
D000818:Animals; D005799:Genes, Dominant; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D050839:Interferon Regulatory Factor-7; D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; D014763:Viral Matrix Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases