Autocrine amplification of type I interferon gene expression mediated by interferon stimulated gene factor 3 (ISGF3).
Interferon regulatory factor (IRF)-1 and IRF-2 have been implicated for the virus-induced expression of the interferon-alpha and beta (type I IFN) genes. However, recent gene disruption studies in mice suggested the presence of other factor(s) interacting with overlapping promoter elements. In the present paper, we describe the characterization of a DNA binding factor which is strongly induced after virus infection and recognizes these promoter elements. After extensive purification, the factor was revealed to be identical to IFN-stimulated gene factor 3 (ISGF3), a transcription factor complex activated by IFN treatment. ISGF3 binds to the promoter element of IFN-beta, positive regulatory domain I (PRDI), with significantly higher affinity than IRF-1, 2, and mutational analysis of PRDI showed that the gene expression and binding of ISGF3, but not of IRF-1, 2, are highly correlated. Furthermore, our functional analysis involving a dominant negative inhibitor for ISGF3 activation and an anti-IFN neutralizing antibody clearly demonstrated the presence of a positive feedback path way for type I IFN genes mediated by ISGF3.
Yoneyama
M
M
Department of Tumor Cell Biology, Tokyo Metropolitan Institute of Medical Science.
Suhara
W
W
Fukuhara
Y
Y
Sato
M
M
Ozato
K
K
Fujita
T
T
D000818:Animals; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005246:Feedback; D005786:Gene Expression Regulation / Q000235:genetics*; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D007370:Interferon Type I / Q000235:genetics* / Q000502:physiology; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007739:L Cells; D051379:Mice; D009522:Newcastle disease virus / Q000254:growth & development; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014775:Virus Activation
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; C494258:Irf1 protein, mouse; C494230:Irf2 protein, mouse; C494228:Isgf3g protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D004247:DNA