WDFY1 mediates TLR3/4 signaling by recruiting TRIF

EMBO Rep. 2015 Apr;16(4):447-55. doi: 10.15252/embr.201439637. Epub 2015 Mar 3.

Abstract

Toll-like receptors (TLRs) are pattern recognition receptors that sense a variety of pathogens, initiate innate immune responses, and direct adaptive immunity. All TLRs except TLR3 recruit the adaptor MyD88 to ultimately elicit inflammatory gene expression, whereas TLR3 and internalized TLR4 use TIR-domain-containing adaptor TRIF for the induction of type I interferon and inflammatory cytokines. Here, we identify the WD repeat and FYVE-domain-containing protein WDFY1 as a crucial adaptor protein in the TLR3/4 signaling pathway. Overexpression of WDFY1 potentiates TLR3- and TLR4-mediated activation of NF-κB, interferon regulatory factor 3 (IRF3), and production of type I interferons and inflammatory cytokines. WDFY1 depletion has the opposite effect. WDFY1 interacts with TLR3 and TLR4 and mediates the recruitment of TRIF to these receptors. Our findings suggest a crucial role for WDFY1 in bridging the TLR-TRIF interaction, which is necessary for TLR signaling.

Keywords: TLR; TRIF; WDFY1; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport / genetics*
  • Adaptor Proteins, Vesicular Transport / immunology
  • Amino Acid Motifs
  • Cytokines / genetics
  • Cytokines / immunology
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Interferon Inducers / pharmacology
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / immunology
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Molecular Sequence Data
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / immunology
  • Plasmids / chemistry
  • Plasmids / immunology
  • Poly I-C / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Toll-Like Receptor 3 / genetics*
  • Toll-Like Receptor 3 / immunology
  • Toll-Like Receptor 4 / genetics*
  • Toll-Like Receptor 4 / immunology
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / immunology
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Cytokines
  • IRF3 protein, human
  • Interferon Inducers
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Nuclear Proteins
  • RNA, Small Interfering
  • TICAM1 protein, human
  • TLR3 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Transcription Factors
  • WDFY1 protein, human
  • Poly I-C