WDFY1 mediates TLR3/4 signaling by recruiting TRIF

Yun Hong Hu, Yu Zhang, Li Qun Jiang, Shuai Wang, Cao Qi Lei, Ming Shun Sun, Hong Bing Shu, Yu Liu

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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. Synopsis This study identifies a new important component of the TLR3/4 signaling pathway. Endosomal membrane protein WDFY1 interacts with both Toll-like receptors and recruits the adaptor TRIF, enabling downstream signaling. WDFY1 potentiates IRF3 and NF-kB activation, as well as type I IFN and inflammatory cytokine production in response to poly(I:C) and LPS. WDFY1 interacts with TLR3 and TLR4 in endosomal membranes of mouse macrophages upon stimulation, but not in resting cells. WDFY1 recruits TRIF to TLR3 and TLR4 in a FYVE-domain-dependent manner. This study identifies a new important component of the TLR3/4 signaling pathway. Endosomal membrane protein WDFY1 interacts with both Toll-like receptors upon ligand binding, and recruits the adaptor TRIF, enabling downstream signaling.

Original languageEnglish (US)
Pages (from-to)447-455
Number of pages9
JournalEMBO Reports
Volume16
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

Keywords

  • TLR
  • TRIF
  • WDFY1
  • signal transduction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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