Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR

J Biol Chem. 2003 May 9;278(19):16713-9. doi: 10.1074/jbc.M300562200. Epub 2003 Feb 27.

Abstract

Recent studies show that a member of the interleukin-1 (IL-1)/Toll receptor superfamily, Toll-like receptor 3 (TLR3), recognizes double-stranded RNA (dsRNA). Because of the similarity in their cytoplasmic domains, IL-1/Toll receptors share signaling components that associate with the IL-1 receptor, including IL-1 receptor-associated kinase (IRAK), MyD88, and TRAF6. However, we find that, in response to dsRNA, TLR3 can mediate the activation of both NFkappaB and mitogen-activated protein (MAP) kinases in IL-1-unresponsive mutant cell lines, including IRAK-deficient I1A and I3A cells, which are defective in a component that is downstream of IL-1R but upstream of IRAK. These results clearly indicate that TLR3 does not simply share the signaling components employed by the IL-1 receptor. Through biochemical analyses we have identified an IRAK-independent TLR3-mediated pathway. Upon binding of dsRNA to TLR3, TRAF6, TAK1, and TAB2 are recruited to the receptor to form a complex, which then translocates to the cytosol where TAK1 is phosphorylated and activated. The dsRNA-dependent protein kinase (PKR) is also detected in this signal-induced TAK1 complex. Kinase inactive mutants of TAK1 (TAK1DN) and PKR (PKRDN) inhibit poly(dI.dC)-induced TLR3-mediated NFkappaB activation, suggesting that both of these kinases play important roles in this pathway.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Carrier Proteins / metabolism
  • Humans
  • Interleukin-1 Receptor-Associated Kinases
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System
  • Membrane Glycoproteins / metabolism*
  • Mice
  • NF-kappa B / metabolism*
  • Protein Kinases / metabolism*
  • Proteins / metabolism
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction*
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • eIF-2 Kinase / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • Proteins
  • Receptors, Cell Surface
  • TAB2 protein, human
  • TLR3 protein, human
  • TNF Receptor-Associated Factor 6
  • Tab2 protein, mouse
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • Protein Kinases
  • Interleukin-1 Receptor-Associated Kinases
  • eIF-2 Kinase
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7