Nucleoredoxin negatively regulates Toll-like receptor 4 signaling via recruitment of flightless-I to myeloid differentiation primary response gene (88).
We previously characterized nucleoredoxin (NRX) as a negative regulator of the Wnt signaling pathway through Dishevelled (Dvl). We perform a comprehensive search for other NRX-interacting proteins and identify Flightless-I (Fli-I) as a novel NRX-binding partner. Fli-I binds to NRX and other related proteins, such as Rod-derived cone viability factor (RdCVF), whereas Dvl binds only to NRX. Endogenous NRX and Fli-I in vivo interactions are confirmed. Both NRX and RdCVF link Fli-I with myeloid differentiation primary response gene (88) (MyD88), an important adaptor protein for innate immune response. NRX and RdCVF also potentiate the negative effect of Fli-I upon lipopolysaccharide-induced activation of NF-kappaB through the Toll-like receptor 4/MyD88 pathway. Embryonic fibroblasts derived from NRX gene-targeted mice show aberrant NF-kappaB activation upon lipopolysaccharide stimulation. These results suggest that the NRX subfamily of proteins forms a link between MyD88 and Fli-I to mediate negative regulation of the Toll-like receptor 4/MyD88 pathway.
Hayashi
Tatsuya
T
Laboratory of Intracellular Signaling, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Funato
Yosuke
Y
Terabayashi
Takeshi
T
Morinaka
Akifumi
A
Sakamoto
Reiko
R
Ichise
Hirotake
H
Fukuda
Hiroyuki
H
Yoshida
Nobuaki
N
Miki
Hiroaki
H
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D010088:Oxidoreductases / Q000737:chemistry / Q000502:physiology*; D011485:Protein Binding; D051789:Proto-Oncogene Protein c-fli-1 / Q000096:biosynthesis*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
C497426:Fli1 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009687:Nuclear Proteins; D051789:Proto-Oncogene Protein c-fli-1; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D010088:Oxidoreductases; C105231:nucleoredoxin
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