Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-κB-independent

Nan Wang, Qingming Dong, Jingjing Li, Rohit K. Jangra, Meiyun Fan, Allan R. Brasier, Stanley M. Lemon, Lawrence M. Pfeffer, Kui Li

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The zinc finger antiviral protein (ZAP) is an interferon-stimulated gene that restricts the replication of retroviruses, alpha-viruses, and filoviruses. Relatively little is known, however, regarding the detailed mechanism of ZAP induction during viral infections. We show that, although being inducible by either interferon or virus, expression of ZAP is more efficiently activated by virus than are several other classical interferon-stimulated genes and that viral induction of ZAP occurs under the direct control of interferon regulatory factor 3 (IRF3) independent of interferon paracrine/autocrine signaling. ZAP was upregulated in cells unresponsive to type I and III interferons upon engagement of TLR3, retinoic inducible gene I/melanoma differentiation-associated gene 5 pathways, or ectopic expression of a constitutively active IRF3 mutant. Conversely, induction of ZAP by virus or dsRNA was severely impaired in cells expressing a dominant-negative mutant IRF3 and completely abrogated in cells lacking IRF3. In contrast to IRF3, ZAP induction was independent of NF-κB activity. Mutational analysis of the human ZAP promoter revealed that multiple interferon-stimulated response elements far distal to the transcription start site serve redundantly to control IRF3-dependent induction of ZAP transcription. Chromatin immunoprecipitation assays demonstrated that IRF3 selectively binds the distal interferon-stimulated response elements in human ZAP promoter following viral infection. Collectively, these data suggest that ZAP is a direct target gene of IRF3 action in cellular antiviral responses.

Original languageEnglish (US)
Pages (from-to)6080-6090
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number9
DOIs
StatePublished - Feb 26 2010

Fingerprint

Interferon Regulatory Factor-3
Zinc Fingers
Antiviral Agents
Zinc
Interferons
Proteins
Viruses
Genes
Response Elements
Virus Diseases
Autocrine Communication
Paracrine Communication
Alphavirus
Interferon Type I
Viral Genes
Chromatin Immunoprecipitation
Transcription Initiation Site
Retroviridae
Transcription
Chromatin

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Wang, N., Dong, Q., Li, J., Jangra, R. K., Fan, M., Brasier, A. R., ... Li, K. (2010). Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-κB-independent. Journal of Biological Chemistry, 285(9), 6080-6090. https://doi.org/10.1074/jbc.M109.054486

Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-κB-independent. / Wang, Nan; Dong, Qingming; Li, Jingjing; Jangra, Rohit K.; Fan, Meiyun; Brasier, Allan R.; Lemon, Stanley M.; Pfeffer, Lawrence M.; Li, Kui.

In: Journal of Biological Chemistry, Vol. 285, No. 9, 26.02.2010, p. 6080-6090.

Research output: Contribution to journalArticle

Wang, N, Dong, Q, Li, J, Jangra, RK, Fan, M, Brasier, AR, Lemon, SM, Pfeffer, LM & Li, K 2010, 'Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-κB-independent', Journal of Biological Chemistry, vol. 285, no. 9, pp. 6080-6090. https://doi.org/10.1074/jbc.M109.054486
Wang, Nan ; Dong, Qingming ; Li, Jingjing ; Jangra, Rohit K. ; Fan, Meiyun ; Brasier, Allan R. ; Lemon, Stanley M. ; Pfeffer, Lawrence M. ; Li, Kui. / Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-κB-independent. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 9. pp. 6080-6090.
@article{0d8d8200927b4e388a480d3d71f4377a,
title = "Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-κB-independent",
abstract = "The zinc finger antiviral protein (ZAP) is an interferon-stimulated gene that restricts the replication of retroviruses, alpha-viruses, and filoviruses. Relatively little is known, however, regarding the detailed mechanism of ZAP induction during viral infections. We show that, although being inducible by either interferon or virus, expression of ZAP is more efficiently activated by virus than are several other classical interferon-stimulated genes and that viral induction of ZAP occurs under the direct control of interferon regulatory factor 3 (IRF3) independent of interferon paracrine/autocrine signaling. ZAP was upregulated in cells unresponsive to type I and III interferons upon engagement of TLR3, retinoic inducible gene I/melanoma differentiation-associated gene 5 pathways, or ectopic expression of a constitutively active IRF3 mutant. Conversely, induction of ZAP by virus or dsRNA was severely impaired in cells expressing a dominant-negative mutant IRF3 and completely abrogated in cells lacking IRF3. In contrast to IRF3, ZAP induction was independent of NF-κB activity. Mutational analysis of the human ZAP promoter revealed that multiple interferon-stimulated response elements far distal to the transcription start site serve redundantly to control IRF3-dependent induction of ZAP transcription. Chromatin immunoprecipitation assays demonstrated that IRF3 selectively binds the distal interferon-stimulated response elements in human ZAP promoter following viral infection. Collectively, these data suggest that ZAP is a direct target gene of IRF3 action in cellular antiviral responses.",
author = "Nan Wang and Qingming Dong and Jingjing Li and Jangra, {Rohit K.} and Meiyun Fan and Brasier, {Allan R.} and Lemon, {Stanley M.} and Pfeffer, {Lawrence M.} and Kui Li",
year = "2010",
month = "2",
day = "26",
doi = "10.1074/jbc.M109.054486",
language = "English (US)",
volume = "285",
pages = "6080--6090",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "9",

}

TY - JOUR

T1 - Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-κB-independent

AU - Wang, Nan

AU - Dong, Qingming

AU - Li, Jingjing

AU - Jangra, Rohit K.

AU - Fan, Meiyun

AU - Brasier, Allan R.

AU - Lemon, Stanley M.

AU - Pfeffer, Lawrence M.

AU - Li, Kui

PY - 2010/2/26

Y1 - 2010/2/26

N2 - The zinc finger antiviral protein (ZAP) is an interferon-stimulated gene that restricts the replication of retroviruses, alpha-viruses, and filoviruses. Relatively little is known, however, regarding the detailed mechanism of ZAP induction during viral infections. We show that, although being inducible by either interferon or virus, expression of ZAP is more efficiently activated by virus than are several other classical interferon-stimulated genes and that viral induction of ZAP occurs under the direct control of interferon regulatory factor 3 (IRF3) independent of interferon paracrine/autocrine signaling. ZAP was upregulated in cells unresponsive to type I and III interferons upon engagement of TLR3, retinoic inducible gene I/melanoma differentiation-associated gene 5 pathways, or ectopic expression of a constitutively active IRF3 mutant. Conversely, induction of ZAP by virus or dsRNA was severely impaired in cells expressing a dominant-negative mutant IRF3 and completely abrogated in cells lacking IRF3. In contrast to IRF3, ZAP induction was independent of NF-κB activity. Mutational analysis of the human ZAP promoter revealed that multiple interferon-stimulated response elements far distal to the transcription start site serve redundantly to control IRF3-dependent induction of ZAP transcription. Chromatin immunoprecipitation assays demonstrated that IRF3 selectively binds the distal interferon-stimulated response elements in human ZAP promoter following viral infection. Collectively, these data suggest that ZAP is a direct target gene of IRF3 action in cellular antiviral responses.

AB - The zinc finger antiviral protein (ZAP) is an interferon-stimulated gene that restricts the replication of retroviruses, alpha-viruses, and filoviruses. Relatively little is known, however, regarding the detailed mechanism of ZAP induction during viral infections. We show that, although being inducible by either interferon or virus, expression of ZAP is more efficiently activated by virus than are several other classical interferon-stimulated genes and that viral induction of ZAP occurs under the direct control of interferon regulatory factor 3 (IRF3) independent of interferon paracrine/autocrine signaling. ZAP was upregulated in cells unresponsive to type I and III interferons upon engagement of TLR3, retinoic inducible gene I/melanoma differentiation-associated gene 5 pathways, or ectopic expression of a constitutively active IRF3 mutant. Conversely, induction of ZAP by virus or dsRNA was severely impaired in cells expressing a dominant-negative mutant IRF3 and completely abrogated in cells lacking IRF3. In contrast to IRF3, ZAP induction was independent of NF-κB activity. Mutational analysis of the human ZAP promoter revealed that multiple interferon-stimulated response elements far distal to the transcription start site serve redundantly to control IRF3-dependent induction of ZAP transcription. Chromatin immunoprecipitation assays demonstrated that IRF3 selectively binds the distal interferon-stimulated response elements in human ZAP promoter following viral infection. Collectively, these data suggest that ZAP is a direct target gene of IRF3 action in cellular antiviral responses.

UR - http://www.scopus.com/inward/record.url?scp=77949899515&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77949899515&partnerID=8YFLogxK

U2 - 10.1074/jbc.M109.054486

DO - 10.1074/jbc.M109.054486

M3 - Article

VL - 285

SP - 6080

EP - 6090

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 9

ER -