WDFY1 mediates TLR3/4 signaling by recruiting TRIF.
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.
State Key Laboratory of Virology, Medical Research Institute College of Life Sciences Wuhan University, Wuhan, China.
Yun-Hong
YH
Hu
State Key Laboratory of Virology, Medical Research Institute College of Life Sciences Wuhan University, Wuhan, China.
Yu
Y
Zhang
State Key Laboratory of Virology, Medical Research Institute College of Life Sciences Wuhan University, Wuhan, China.
Li-Qun
LQ
Jiang
State Key Laboratory of Virology, Medical Research Institute College of Life Sciences Wuhan University, Wuhan, China.
Shuai
S
Wang
State Key Laboratory of Virology, Medical Research Institute College of Life Sciences Wuhan University, Wuhan, China.
Cao-Qi
CQ
Lei
State Key Laboratory of Virology, Medical Research Institute College of Life Sciences Wuhan University, Wuhan, China.
Ming-Shun
MS
Sun
State Key Laboratory of Virology, Medical Research Institute College of Life Sciences Wuhan University, Wuhan, China.
Hong-Bing
HB
Shu
State Key Laboratory of Virology, Medical Research Institute College of Life Sciences Wuhan University, Wuhan, China yuliu@whu.edu.cn.
Yu
Y
Liu
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000276:immunology; D020816:Amino Acid Motifs; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D010957:Plasmids / Q000737:chemistry / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; C494232:IRF3 protein, human; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; C000603634:WDFY1 protein, human; D011070:Poly I-C
TLR; TRIF; WDFY1; signal transduction