HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival during viral infections

Lei Sun, Zhengfan Jiang, Victoria A. Acosta-Rodriguez, Michael Berger, Xin Du, Jin Huk Choi, Jianhui Wang, Kuan wen Wang, Gokhul K. Kilaru, Jennifer A. Mohawk, Jiexia Quan, Lindsay Scott, Sara Hildebrand, Xiaohong Li, Miao Tang, Xiaoming Zhan, Anne R. Murray, Diantha La Vine, Eva Marie Y. Moresco, Joseph S. TakahashiBruce Beutler

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Transcriptional regulation of numerous interferon-regulated genes, including Toll-like receptor 3 (Tlr3), which encodes an innate immune sensor of viral double-stranded RNA, depends on the interferon regulatory factor 1 (IRF1) and IRF2 transcription factors. We detected specific abrogation of macrophage responses to polyinosinic-polycytidylic acid (poly(I:C)) resulting from three independent N-ethyl-N-nitrosourea-induced mutations in host cell factor C2 (Hcfc2). Hcfc2 mutations compromised survival during influenza virus and herpes simplex virus 1 infections. HCFC2 promoted the binding of IRF1 and IRF2 to the Tlr3 promoter, without which inflammatory cytokine and type I IFN responses to the double-stranded RNA analogue poly(I:C) are reduced in mouse macrophages. HCFC2 was also necessary for the transcription of a large subset of other IRF2-dependent interferon-regulated genes. Deleterious mutations of Hcfc2 may therefore increase susceptibility to diverse infectious diseases.

Original languageEnglish (US)
Pages (from-to)3263-3277
Number of pages15
JournalJournal of Experimental Medicine
Volume214
Issue number11
DOIs
StatePublished - Nov 1 2017

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Sun, L., Jiang, Z., Acosta-Rodriguez, V. A., Berger, M., Du, X., Choi, J. H., Wang, J., Wang, K. W., Kilaru, G. K., Mohawk, J. A., Quan, J., Scott, L., Hildebrand, S., Li, X., Tang, M., Zhan, X., Murray, A. R., Vine, D. L., Moresco, E. M. Y., ... Beutler, B. (2017). HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival during viral infections. Journal of Experimental Medicine, 214(11), 3263-3277. https://doi.org/10.1084/jem.20161630