SARM:TRIF:activated TLR3/TLR4 TRIF:activated TLR3/TLR4 Negative regulator SARM binds to TRIF Authored: Shamovsky, V, 2012-05-15 Edited: Shamovsky, V, 2012-11-19 Pubmed16964262 Pubmed19656901 Reactome Database ID Release 432559568 Reactome, http://www.reactome.org ReactomeREACT_150310 Reviewed: Fitzgerald, Katherine A, 2012-11-13 SARM (sterile alpha-and armadillo-motif-containing protein) is a TIR-domain-containing adaptor, which functions as a negative regulator of TRIF-dependent Toll-like receptor signaling in humans. LPS treatment led to a rapid increase of the SARM expression in peripheral blood mononuclear cells (PBMCs) and as a result an increased association between SARM and TRIF. SARM expression was also shown to inhibit poly(I:C)-induced TRIF-dependent NF-kB activaion, RANTES production and IRF activation in human embryonic kidney HEK293 cells [Carty M et al 2006]. Moreover, suppression of endogenous SARM expression by siRNA led to enhanced TLR3- and TLR4-dependent gene induction in both transformed HEK293 and primary PBMC cells, while endotoxin-tolerant human monocytes showed increased expression of SARM and decreased activation of TRIF-dependent cytokines [Carty M et al 2006; Piao W et al 2009]. Thus, SARM inhibits TLR4 and TLR3 signaling by targeting TRIF. The complex of TRIF:SARM is thought to inhibit downstream TRIF signaling by preventing the recruitment of TRIF effector proteins [Carty M et al 2006].