Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling.
Tumor necrosis factor receptor-associated factor 6 (TRAF6) transduces signals from members of the Toll/interleukin-1 (IL-1) receptor family by interacting with IL-1 receptor-associated kinase-1 (IRAK-1) after IRAK-1 is released from the receptor-MyD88 complex upon IL-1 stimulation. However, the molecular mechanisms underlying regulation of the IRAK-1/TRAF6 interaction are largely unknown. We have identified TIFA, a TRAF-interacting protein with a forkhead-associated (FHA) domain. The FHA domain is a motif known to bind directly to phosphothreonine and phosphoserine. In transient transfection assays, TIFA activates NFkappaBeta and c-Jun amino-terminal kinase. However, TIFA carrying a mutation that abolishes TRAF6 binding or mutations in the FHA domain that are known to abolish FHA domain binding to phosphopeptide fails to activate NFkappaBeta and c-Jun amino-terminal kinase. TIFA, when overexpressed, binds both TRAF6 and IRAK-1 and significantly enhances the IRAK-1/TRAF6 interaction. Furthermore, analysis of endogenous proteins indicates that TIFA associates with TRAF6 constitutively, whereas it associates with IRAK-1 in an IL-1 stimulation-dependent manner in vivo. Thus, TIFA is likely to mediate IRAK-1/TRAF6 interaction upon IL-1 stimulation.
Takatsuna
Hiroshi
H
Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Kato
Hiroki
H
Gohda
Jin
J
Akiyama
Taishin
T
Moriya
Ayaka
A
Okamoto
Yoshinari
Y
Yamagata
Yuriko
Y
Otsuka
Masami
M
Umezawa
Kazuo
K
Semba
Kentaro
K
Inoue
Jun-Ichiro
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D007375:Interleukin-1 / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D011506:Proteins; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; C499176:T2bp protein, mouse; D048029:TNF Receptor-Associated Factor 6; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases