Interferon regulatory factor 5 represses expression of the Epstein-Barr virus oncoprotein LMP1: braking of the IRF7/LMP1 regulatory circuit.
We have reported evidence for a positive regulatory circuit between interferon regulatory factor 7 (IRF7) and the Epstein-Barr virus (EBV) oncoprotein 1 (LMP1) (S. Ning, A. M. Hahn, and J. S. Pagano, J. Virol. 77:9359-9368, 2003). To explore a possible braking mechanism for this circuit, several type II EBV-infected cell lines that express different levels of LMP1 and IRF7 proteins and therefore are convenient for studying modulation of expression of LMP1 were analyzed. Endogenous levels of IRF7 and LMP1 were directly correlated. Transient expression of an IRF7 dominant-negative mutant decreased LMP1 levels. Endogenous IRF5 and IRF7 proteins were shown to physically associate in EBV-positive cells. Transient expression of IRF5 decreased activation of the LMP1 promoter by IRF7 in a dose-dependent manner. Finally, transfection of either an IRF5 dominant-negative construct or IRF5 small interfering RNA in these cells resulted in increases in endogenous levels of LMP1. These results indicate that IRF5 can downregulate IRF7's induction of expression of LMP1 most likely by interacting with IRF7 and provide a means of modulating a regulatory circuit between IRF7 and LMP1.
Ning
Shunbin
S
Lineberger Comprehensive Cancer Center, University of North Carolina, School of Medicine, Campus Box 7295, Chapel Hill, NC 27599, USA.
Huye
Leslie E
LE
Pagano
Joseph S
JS
D000956:Antigens, Viral / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D015870:Gene Expression; D005809:Genes, Regulator; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000276:immunology; D006801:Humans; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D008954:Models, Biological; D009154:Mutation; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000276:immunology
D000956:Antigens, Viral; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C431713:IRF5 protein, human; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014763:Viral Matrix Proteins