SARM inhibits both TRIF- and MyD88-mediated AP-1 activation

Eur J Immunol. 2010 Jun;40(6):1738-47. doi: 10.1002/eji.200940034.


SARM (sterile alpha- and armadillo-motif-containing protein), the fifth identified TIR (Toll-interleukin 1 receptor (IL-1R)) domain-containing adaptors in humans, downregulates NF-kappaB and IRF3 (interferon-regulatory factor 3)-mediated TLR3 and TLR4 signaling. SARM was characterized as a negative regulator of the TRIF (TIR-domain-containing adaptor protein inducing IFN-beta)-dependent pathway via its interaction with TRIF. However, the precise mechanism of action of SARM remains unclear. Here, we demonstrate that SARM inhibits MAPK activation in human embryonic kidney 293 cells, and U937 cells. Both the TRIF- and MyD88-mediated, as well as basal MAPK activity, were repressed, indicating that SARM-mediated inhibition may not be exclusively directed at TRIF or MyD88, but that SARM may also directly inhibit MAPK phosphorylation. The MAPK inhibition effect was verified by RNAi, which increased the basal level of AP-1. Furthermore, LPS challenge upregulated SARM at both the mRNA and protein levels. Finally, we provide evidence to show that truncated SARM changes its subcellular localization, suggesting the importance of the N-terminal and sterile alpha motif domains in the autoregulation of SARM activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / immunology
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Armadillo Domain Proteins / immunology
  • Armadillo Domain Proteins / metabolism*
  • Cell Line
  • Cytoskeletal Proteins / immunology
  • Cytoskeletal Proteins / metabolism*
  • Enzyme Activation / physiology
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunoblotting
  • Microscopy, Confocal
  • Mitogen-Activated Protein Kinase Kinases / immunology
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Myeloid Differentiation Factor 88 / immunology
  • Myeloid Differentiation Factor 88 / metabolism*
  • Phosphorylation
  • RNA, Small Interfering
  • Signal Transduction / immunology*
  • Transcription Factor AP-1 / immunology
  • Transcription Factor AP-1 / metabolism*
  • U937 Cells


  • Adaptor Proteins, Vesicular Transport
  • Armadillo Domain Proteins
  • Cytoskeletal Proteins
  • Myeloid Differentiation Factor 88
  • RNA, Small Interfering
  • SARM1 protein, human
  • TICAM1 protein, human
  • Transcription Factor AP-1
  • Mitogen-Activated Protein Kinase Kinases