Reactome | SARM binds TICAM1:TRAM:TLR4:LY96:LPS:CD14

SARM binds TICAM1:TRAM:TLR4:LY96:LPS:CD14

Stable Identifier

R-HSA-2559568

Type

Reaction [binding]

Species

Homo sapiens

Compartment

endosome membrane, cytosol

Synonyms

Negative regulator SARM binds to TRIF within activated TLR4 complex

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SARM binds TICAM1:TRAM:TLR4:LY96:LPS:CD14

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SARM (sterile alpha-and armadillo-motif-containing protein) is a TIR-domain-containing adaptor, which functions as a negative regulator of TRIF (TICAM1)-dependent Toll-like receptor signaling in humans. A pairwise yeast two-hybrid assay demonstrated that SARM is capable of binding directly to TICAM1 (Carty M et al. 2006). GST pulldown studies suggest that protein-protein interactions occur between the TIR domains of SARM and TICAM1 (Carlsson E et al. 2016). The complex of TICAM1:SARM is thought to inhibit downstream TRIF signaling by preventing the recruitment of TRIF effector proteins (Carty M et al. 2006).

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 TICAM1 (Carty M et al. 2006). Moreover, suppression of endogenous SARM expression by siRNA led to enhanced 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 TICAM1-dependent cytokines (Carty M et al. 2006; Piao W et al. 2009). Thus, SARM negatively regulates TICAM1 (TRIF)-dependent TLR4 signaling pathway.

Literature References

PubMed ID	Title	Journal	Year
16964262	The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling Carty, M, Goodbody, R, Schröder, M, Stack, J, Moynagh, PN, Bowie, AG	Nat. Immunol.	2006
19656901	Endotoxin tolerance dysregulates MyD88- and Toll/IL-1R domain-containing adapter inducing IFN-beta-dependent pathways and increases expression of negative regulators of TLR signaling Piao, W, Song, C, Chen, H, Diaz, MA, Wahl, LM, Fitzgerald, KA, Li, L, Medvedev, AE	J. Leukoc. Biol.	2009