The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling

Nat Immunol. 2006 Oct;7(10):1074-81. doi: 10.1038/ni1382. Epub 2006 Sep 10.

Abstract

Toll-like receptors discriminate between different pathogen-associated molecules and activate signaling cascades that lead to immune responses. The specificity of Toll-like receptor signaling occurs by means of adaptor proteins containing Toll-interleukin 1 receptor (TIR) domains. Activating functions have been assigned to four TIR adaptors: MyD88, Mal, TRIF and TRAM. Here we characterize a fifth TIR adaptor, SARM, as a negative regulator of TRIF-dependent Toll-like receptor signaling. Expression of SARM blocked gene induction 'downstream' of TRIF but not of MyD88. SARM associated with TRIF, and 'knockdown' of endogenous SARM expression by interfering RNA led to enhanced TRIF-dependent cytokine and chemokine induction. Thus, the fifth mammalian TIR adaptor SARM is a negative regulator of Toll-like receptor signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / antagonists & inhibitors*
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Armadillo Domain Proteins / antagonists & inhibitors
  • Armadillo Domain Proteins / genetics
  • Armadillo Domain Proteins / metabolism*
  • Cells, Cultured
  • Chemokines / genetics
  • Cytokines / genetics*
  • Cytoskeletal Proteins / antagonists & inhibitors
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Interferon Regulatory Factor-7 / antagonists & inhibitors
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism
  • Protein Structure, Tertiary / genetics
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Signal Transduction / genetics
  • Toll-Like Receptor 3 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptors / metabolism*
  • Transcriptional Activation

Substances

  • Adaptor Proteins, Vesicular Transport
  • Armadillo Domain Proteins
  • Chemokines
  • Cytokines
  • Cytoskeletal Proteins
  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • RNA, Small Interfering
  • SARM1 protein, human
  • TICAM1 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptors