TRIFs

TRIFs, or TIR-domain-containing adaptor proteins inducing interferon-β, designate a class of cytosolic adaptors that relay signals from Toll-like receptors to transcriptional programs, particularly type I interferons. The best-characterized member is TRIF, also called TICAM1 (Toll/IL-1 receptor domain-containing adaptor molecule 1). In humans, the TICAM1 gene encodes TRIF, which is expressed in many immune cells including dendritic cells and macrophages.

In TLR signaling, TRIF acts downstream of TLR3 and, in endosomal TLR4 signaling, within the MyD88-independent pathway. It recruits TBK1 and IKKε to activate IRF3, inducing IFN-β and ISGs. It also engages TRAF3 for IRF3 activity and interfaces with RIP1 and TRAF6 to promote NF-κB signaling. A RHIM motif enables interactions with RIP1 and RIP3, linking TRIF to necroptotic pathways in certain contexts.

Structure and regulation: TRIF contains a C-terminal TIR domain for downstream recruitment and an N-terminal signaling region, including a RHIM motif. It is regulated by ubiquitination and transcriptional control. TRIF is one of several TIR-domain adaptors in TLR signaling, with TRAM (TICAM2) acting in conjunction with TRIF for TLR4 endosomal signaling.

Physiological role and clinical relevance: TRIF-dependent signaling is crucial for antiviral defense, especially against dsRNA. Defects reduce type I interferon responses and alter inflammatory signaling, with implications for infection, autoimmunity, and inflammatory diseases. Therapies that modulate TRIF pathways are under investigation.