TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway

Nat Immunol. 2003 Nov;4(11):1144-50. doi: 10.1038/ni986. Epub 2003 Oct 12.

Abstract

Recognition of pathogens by Toll-like receptors (TLRs) triggers innate immune responses through signaling pathways mediated by Toll-interleukin 1 receptor (TIR) domain-containing adaptors such as MyD88, TIRAP and TRIF. MyD88 is a common adaptor that is essential for proinflammatory cytokine production, whereas TRIF mediates the MyD88-independent pathway from TLR3 and TLR4. Here we have identified a fourth TIR domain-containing adaptor, TRIF-related adaptor molecule (TRAM), and analyzed its physiological function by gene targeting. TRAM-deficient mice showed defects in cytokine production in response to the TLR4 ligand, but not to other TLR ligands. TLR4- but not TLR3-mediated MyD88-independent interferon-beta production and activation of signaling cascades were abolished in TRAM-deficient cells. Thus, TRAM provides specificity for the MyD88-independent component of TLR4 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation / metabolism
  • B-Lymphocytes / physiology
  • Cytokines / biosynthesis
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Molecular Sequence Data
  • Myeloid Differentiation Factor 88
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic / metabolism
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction / physiology*
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptors

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Cytokines
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Receptors, Interleukin-1
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • TRAM protein, ER, mammalian

Associated data

  • GENBANK/AY232653