Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms: Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function

Margo E. Mancl, Guodong Hu, Niquiche Sangster-Guity, Stacey L. Olshalsky, Katherine Hoops, Patricia Fitzgerald-Bocarsly, Paula M. Pitha, Karen Pinder, Betsy J. Barnes

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)21078-21090
Number of pages13
JournalJournal of Biological Chemistry
Volume280
Issue number22
DOIs
StatePublished - Jun 3 2005

Fingerprint

Interferon Regulatory Factors
Protein Isoforms
Viruses
Exons
Blood Cells
Blood
Binding Sites
Interferon Type I
T-cells
Transcription Initiation Site
Gene expression
Dendritic Cells
Genes
Neoplasms
Consensus
B-Lymphocytes
Chemical activation
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Mancl, Margo E. ; Hu, Guodong ; Sangster-Guity, Niquiche ; Olshalsky, Stacey L. ; Hoops, Katherine ; Fitzgerald-Bocarsly, Patricia ; Pitha, Paula M. ; Pinder, Karen ; Barnes, Betsy J. / Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms : Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 22. pp. 21078-21090.
@article{47a7fb85203545b0b93917b512b1bce3,
title = "Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms: Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function",
abstract = "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.",
author = "Mancl, {Margo E.} and Guodong Hu and Niquiche Sangster-Guity and Olshalsky, {Stacey L.} and Katherine Hoops and Patricia Fitzgerald-Bocarsly and Pitha, {Paula M.} and Karen Pinder and Barnes, {Betsy J.}",
year = "2005",
month = "6",
day = "3",
doi = "10.1074/jbc.M500543200",
language = "English (US)",
volume = "280",
pages = "21078--21090",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "22",

}

Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms : Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function. / Mancl, Margo E.; Hu, Guodong; Sangster-Guity, Niquiche; Olshalsky, Stacey L.; Hoops, Katherine; Fitzgerald-Bocarsly, Patricia; Pitha, Paula M.; Pinder, Karen; Barnes, Betsy J.

In: Journal of Biological Chemistry, Vol. 280, No. 22, 03.06.2005, p. 21078-21090.

Research output: Contribution to journalArticle

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.

UR - http://www.scopus.com/inward/record.url?scp=20444368020&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20444368020&partnerID=8YFLogxK

U2 - 10.1074/jbc.M500543200

DO - 10.1074/jbc.M500543200

M3 - Article

C2 - 15805103

AN - SCOPUS:20444368020

VL - 280

SP - 21078

EP - 21090

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 22

ER -