Dual functions of interferon regulatory factors 7C in Epstein-Barr virus-mediated transformation of human B lymphocytes.
Epstein-Barr virus (EBV) infection is associated with several human malignancies. Interferon (IFN) regulatory factor 7 (IRF-7) has several splicing variants, and at least the major splicing variant (IRF-7A) has oncogenic potential and is associated with EBV transformation processes. IRF-7C is an alternative splicing variant with only the DNA-binding domain of IRF-7. Whether IRF-7C is present under physiological conditions and its functions in viral transformation are unknown. In this report, we prove the existence of IRF-7C protein and RNA in certain cells under physiological conditions, and find that high levels of IRF-7C are associated with EBV transformation of human primary B cells in vitro as well as EBV type III latency. EBV latent membrane protein 1 (LMP-1) stimulates IRF-7C expression in B lymphocytes. IRF-7C has oncogenic potential in rodent cells and partially restores the growth properties of EBV-transformed cells under a growth-inhibition condition. A tumor array experiment has identified six primary tumor specimens with high levels of IRF-7C protein--all of them are lymphomas. Furthermore, we show that the expression of IRF-7C is apparently closely associated with other IRF-7 splicing variants. IRF-7C inhibits the function of IRF-7 in transcriptional regulation of IFN genes. These data suggest that EBV may use splicing variants of IRF-7 for its transformation process in two strategies: to use oncogenic properties of various IRF-7 splicing variants, but use one of its splicing variants (IRF-7C) to block the IFN-induction function of IRF-7 that is detrimental for viral transformation. The work provides a novel relation of host/virus interactions, and has expanded our knowledge about IRFs in EBV transformation.
Zhao
Yong
Y
School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, United States of America.
Xu
Dongsheng
D
Jiang
Yanjun
Y
Zhang
Luwen
L
D017398:Alternative Splicing; D000818:Animals; D001402:B-Lymphocytes / Q000821:virology*; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D005347:Fibroblasts / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D015533:Transcriptional Activation
D050839:Interferon Regulatory Factor-7