TY - JOUR
T1 - Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms
T2 - Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function
AU - Mancl, Margo E.
AU - Hu, Guodong
AU - Sangster-Guity, Niquiche
AU - Olshalsky, Stacey L.
AU - Hoops, Katherine
AU - Fitzgerald-Bocarsly, Patricia
AU - Pitha, Paula M.
AU - Pinder, Karen
AU - Barnes, Betsy J.
PY - 2005/6/3
Y1 - 2005/6/3
N2 - Interferon regulatory factor-5 (IRF-5) is a mediator of virus-induced immune activation and type I interferon (ZFTV) gene regulation. In human primary plasmacytoid dendritic cells (PDC), IRF-5 is transcribed into four distinct alternatively spliced isoforms (V1, V2, V3, and V4), whereas in human primary peripheral blood mononuclear cells two additional new isoforms (V5 and V6) were identified. The IRF-5 V1, V2, and V3 transcripts have different noncoding first exons and distinct insertion/ deletion patterns in exon 6. Here we showed that V1 and V3 have distinct transcription start sites and are regulated by two discrete promoters. The V1 promoter (P-V1) is constitutively active, contains an IRF-E consensus-binding site, and is further stimulated in virus-infected cells by IRF family members. In contrast, endogenous V3 transcripts were up-regulated by type I IFNs, and the V3 promoter (P-V3) contains an IFN-stimulated responsive element-binding site that confers responsiveness to IFN through binding of the ISGF3 complex. In addition to V5 and V6, we have identified three more alternatively spliced IRF-5 isoforms (V7, V8, and V9); V5 and V6 were expressed in peripheral blood mononuclear cells from healthy donors and in immortalized B and T cell malignancies, whereas expression of V7, V8, and V9 transcripts were detected only in human cancers. The results of this study demonstrated the existence of multiple IRF-5 spliced isoforms with distinct cell type-specific expression, cellular localization, differential regulation, and dissimilar functions in virus-mediated type I IFN gene induction.
AB - Interferon regulatory factor-5 (IRF-5) is a mediator of virus-induced immune activation and type I interferon (ZFTV) gene regulation. In human primary plasmacytoid dendritic cells (PDC), IRF-5 is transcribed into four distinct alternatively spliced isoforms (V1, V2, V3, and V4), whereas in human primary peripheral blood mononuclear cells two additional new isoforms (V5 and V6) were identified. The IRF-5 V1, V2, and V3 transcripts have different noncoding first exons and distinct insertion/ deletion patterns in exon 6. Here we showed that V1 and V3 have distinct transcription start sites and are regulated by two discrete promoters. The V1 promoter (P-V1) is constitutively active, contains an IRF-E consensus-binding site, and is further stimulated in virus-infected cells by IRF family members. In contrast, endogenous V3 transcripts were up-regulated by type I IFNs, and the V3 promoter (P-V3) contains an IFN-stimulated responsive element-binding site that confers responsiveness to IFN through binding of the ISGF3 complex. In addition to V5 and V6, we have identified three more alternatively spliced IRF-5 isoforms (V7, V8, and V9); V5 and V6 were expressed in peripheral blood mononuclear cells from healthy donors and in immortalized B and T cell malignancies, whereas expression of V7, V8, and V9 transcripts were detected only in human cancers. The results of this study demonstrated the existence of multiple IRF-5 spliced isoforms with distinct cell type-specific expression, cellular localization, differential regulation, and dissimilar functions in virus-mediated type I IFN gene induction.
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U2 - 10.1074/jbc.M500543200
DO - 10.1074/jbc.M500543200
M3 - Article
C2 - 15805103
AN - SCOPUS:20444368020
SN - 0021-9258
VL - 280
SP - 21078
EP - 21090
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 22
ER -