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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.

Pubmed ID: 12566447


  • Takatsuna H
  • Kato H
  • Gohda J
  • Akiyama T
  • Moriya A
  • Okamoto Y
  • Yamagata Y
  • Otsuka M
  • Umezawa K
  • Semba K
  • Inoue J


The Journal of biological chemistry

Publication Data

April 4, 2003

Associated Grants


Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Carrier Proteins
  • Female
  • Interleukin-1
  • Interleukin-1 Receptor-Associated Kinases
  • Mice
  • Mice, Inbred ICR
  • Molecular Sequence Data
  • NF-kappa B
  • Protein Kinases
  • Proteins
  • Receptors, Interleukin-1
  • Receptors, Tumor Necrosis Factor
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • TNF Receptor-Associated Factor 6