ELF4 is critical for induction of type I interferon and the host antiviral response

Nat Immunol. 2013 Dec;14(12):1237-46. doi: 10.1038/ni.2756. Epub 2013 Nov 3.

Abstract

Induction of type I interferon is a central event of innate immunity, essential for host defense. Here we report that the transcription factor ELF4 is induced by type I interferon and upregulates interferon expression in a feed-forward loop. ELF4 deficiency leads to reduced interferon production, resulting in enhanced susceptibility to West Nile virus encephalitis in mice. After viral infection, ELF4 is recruited by STING, interacts with and is activated by the MAVS-TBK1 complex, and translocates into the nucleus to bind interferon promoters. Cooperative binding with ELF4 increases the binding affinity of interferon regulatory factors IRF3 and IRF7, which is mediated by EICE elements. Thus, in addition to identifying a regulator of innate immune signaling, we uncovered a role for EICE elements in interferon transactivation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • DNA-Binding Proteins / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunoblotting
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / immunology
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Regulatory Factor-7 / immunology
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon-beta / genetics
  • Interferon-beta / immunology*
  • Interferon-beta / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Protein Binding / immunology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology
  • Survival Analysis
  • Transcription Factors / genetics
  • Transcription Factors / immunology*
  • Transcription Factors / metabolism
  • Transcriptional Activation / immunology
  • West Nile Fever / immunology*
  • West Nile Fever / virology
  • West Nile virus / immunology*
  • West Nile virus / physiology

Substances

  • DNA-Binding Proteins
  • Elf4 protein, mouse
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • MPYS protein, mouse
  • Membrane Proteins
  • Transcription Factors
  • Interferon-beta