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


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.

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Supported by the Irish Research Council for Science, Engineering and Technology and Science Foundation Ireland (Investigator Programme; 02/IN.1/B192).

Author information

M.C. designed and performed most of the experiments and co-wrote the paper; R.G. performed some experiments; M.S. advised on the study; J.S. performed some experiments; P.N.M co-designed and advised on the study and experiments; A.G.B. conceived and co-designed the study, advised on experiments and co-wrote the paper.

Competing interests

The authors declare no competing financial interests.

Correspondence to Andrew G Bowie.

Supplementary information

  1. Supplementary Table 1

    Oligonucleotides used in the study (PDF 42 kb)

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Figure 1: Expression of SARM fails to activate NF-κB or IRF3.
Figure 2: SARM inhibits TRIF dependent NF-κB activation.
Figure 3: SARM inhibits TLR3- and TLR4-dependent gene induction.
Figure 4: SARM inhibits IRF7 activation by the TRIF but not by the MyD88 pathway.
Figure 5: SARM associates with and inhibits TRIF signaling.
Figure 6: The TIR and SAM domains of SARM are critical for TRIF inhibition.
Figure 7: 'Knockdown' of SARM expression enhances TRIF- but not MyD88-dependent gene induction.