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J Exp Med. 2017 Nov 6;214(11):3263-3277. doi: 10.1084/jem.20161630. Epub 2017 Oct 2.

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

Author information

1
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX.
2
Department of Genetics, The Scripps Research Institute, La Jolla, CA.
3
Department of Neuroscience, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX.
4
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX bruce.beutler@utsouthwestern.edu.

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.

PMID:
28970238
PMCID:
PMC5679162
DOI:
10.1084/jem.20161630
[Indexed for MEDLINE]
Free PMC Article

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