Transcriptional Regulation of the Human TRIF (TIR Domain-containing Adaptor Protein Inducing Interferon Beta) Gene

TRIF [TIR (Toll/interleukin-1 receptor) domain-containing adaptor protein inducing interferon beta; also known as TICAM-1 (TIR-containing adaptor molecule-1)] is a key adaptor for TLR3 (Toll-like receptor 3)- and TLR4-mediated signalling. We have performed a detailed annotation of the human TRIF gene and fine analysis of the basal and inducible promoter elements lying 5' to the site of initiation of transcription. Human TRIF maps to chromosome 19p13.3 and is flanked upstream by TIP47, which encodes the mannose 6-phosphate receptor binding protein, and downstream by a gene encoding FEM1a, a human homologue of the Caenorhabditis elegans Feminisation-1 gene. Using promoter-reporter deletion constructs, we identified a distal region with the ability to negatively regulate basal transcription and a proximal region containing an Sp1 (stimulating protein 1) site that confers approx. 75% of basal transcriptional activity. TRIF expression can be induced by multiple stimuli, such as the ligands for TLR2, TLR3 and TLR4, and by the pro-inflammatory cytokines tumour necrosis factor alpha and interleukin-1alpha. All of these stimuli act via an NF-kappaB (nuclear factor-kappaB) motif at position -127. In spite of the presence of a STAT1 (signal transduction and activators of transcription 1) motif at position -330, the addition of type I or type II interferon had no effect on TRIF activity. The human TRIF gene would therefore appear to be regulated primarily by NF-kappaB.