TIR domain-containing adapter molecule 2 (TICAM2)

TIR domain-containing adapter molecule 2 (TICAM2), also known as TRAM, is a cytoplasmic adapter involved in Toll-like receptor 4 (TLR4) signaling, which is fundamental for the innate immune response to Gram-negative bacterial lipopolysaccharide (LPS). TICAM2 contains a central TIR (Toll/interleukin-1 receptor) domain facilitating both homotypic and heterotypic protein interactions necessary for the assembly and activation of TLR4 signaling complexes. Upon LPS detection by TLR4, TICAM2 is recruited through its TIR domain and acts as a sorting adapter to specifically promote downstream activation of type I interferon genes and the transcription factor NF-kappa-B, partly by recruiting and interacting with another adapter, TICAM1 (TRIF). TICAM2 is essential for mounting an efficient anti-microbial inflammatory and interferon response, and is broadly expressed in immune and non-immune tissues. Myristoylation of its N-terminus is key for membrane localization and function. TICAM2 is unique among TIR adapters for lacking a death domain, distinguishing its role from MyD88-based pathways. Loss of TICAM2 impairs the innate immune response, particularly the production of type I interferons and pro-inflammatory cytokines in response to TLR4 agonists.

Other names

TRAMTRIF-related adapter moleculeTIRPTIRAP3MyD88-4Toll-like receptor adaptor molecule 2Toll-like receptor adaptor protein 3Putative NF-kappa-B-activating protein 502Toll/interleukin-1 receptor domain-containing protein

Drugs targeting TLR4-mediated pathways can indirectly affect TICAM2 signaling by blocking TLR4 activation and downstream assembly of TICAM2-dependent complexes, thus inhibiting NF-kappa-B and type I interferon production