title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takatsuna
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.forename: Jin
authors.initials: J
authors.lastname: Gohda
authors.forename: Taishin
authors.initials: T
authors.lastname: Akiyama
authors.forename: Ayaka
authors.initials: A
authors.lastname: Moriya
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Yamagata
authors.forename: Masami
authors.initials: M
authors.lastname: Otsuka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Semba
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Inoue
mesh_terms: 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
chemical_list: 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