Virus-induced heterodimer formation between IRF-5 and IRF-7 modulates assembly of the IFNA enhanceosome in vivo and transcriptional activity of IFNA genes.
Transcription factors of the interferon regulatory factor (IRF) family have been identified as critical mediators of early inflammatory gene transcription in infected cells. We have shown previously that IRF-5, like IRF-3 and IRF-7, is a direct transducer of virus-mediated signaling and plays a role in the expression of multiple cytokines/chemokines. The present study is focused on the molecular mechanisms underlying the formation and function of IRF-5/IRF-7 heterodimers in infected cells. The interaction between IRF-5 and IRF-7 is not cooperative and results in a repression rather than enhancement of IFNA gene transcription. The formation of the IRF-5/IRF-7 heterodimer is dependent on IRF-7 phosphorylation, as shown by the glutathione S-transferase pull-down and immunoprecipitation assays. Mapping of the interaction domain revealed that formation of IRF-5/IRF-7 heterodimers occurs through the amino terminus resulting in a masking of the DNA binding domain, the consequent alteration of the composition of the enhanceosome complex binding to IFNA promoters in vivo, and modulation of the expression profile of IFNA subtypes. Thus, these results indicate that IRF-5 can act as both an activator and a repressor of IFN gene induction dependent on the IRF-interacting partner, and IRF-5 may be a part of the regulatory network that ensures timely expression of the immediate early inflammatory genes.
Barnes
Betsy J
BJ
Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21231, USA. barnebe@jhmi.edu
Field
Ann E
AE
Pitha-Rowe
Paula M
PM
D000818:Animals; D002417:Cattle; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D015967:Gene Expression Regulation, Viral; D006801:Humans; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D009522:Newcastle disease virus / Q000502:physiology*; D029082:Sendai virus / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C431713:IRF5 protein, human; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D014157:Transcription Factors