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

J Biol Chem. 2003 Apr 4;278(14):12144-50. doi: 10.1074/jbc.M300720200. Epub 2003 Feb 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Interleukin-1
  • NF-kappa B
  • Proteins
  • Receptors, Interleukin-1
  • Receptors, Tumor Necrosis Factor
  • T2bp protein, mouse
  • TNF Receptor-Associated Factor 6
  • Protein Kinases
  • Interleukin-1 Receptor-Associated Kinases

Associated data

  • GENBANK/AB062110
  • GENBANK/AB062111