Analysis of a TIR-less splice variant of TRIF reveals an unexpected mechanism of TLR3-mediated signaling.
Recognition of viral RNA by Toll-like receptor 3 (TLR3) triggers activation of the transcription factors NF-kappaB and IRF3 and induction of type I interferons. TRIF is a Toll-interleukin 1 receptor (TIR) domain-containing adapter protein critically involved in TLR3-mediated signaling. It has been shown that TRIF interacts with TLR3 through their respective TIR domains. In this study, we identified a splice variant of TRIF lacking the TIR domain, which is designated as TRIS. Overexpression of TRIS activates NF-kappaB, interferon-stimulated response element (ISRE), and the interferon-beta promoter, whereas knockdown of TRIS inhibited TLR3-mediated signaling, suggesting that TRIS is involved in TLR3-mediated signaling. Furthermore, we identified an N-terminal TBK1-binding motif of TRIS or TRIF that was important for its interaction with TBK1 and ability to activate ISRE. Activation of ISRE by TRIS also needs its dimerization or oligomerization mediated by its C-terminal RIP homotypic interaction motif. Finally, we demonstrated that TRIS was associated with TRIF upon TLR3 activation by poly(I-C). These findings reveal an unexpected mechanism of TLR3-mediated signaling.
Han
Ke-Jun
KJ
National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Yang
Yan
Y
Xu
Liang-Guo
LG
Shu
Hong-Bing
HB
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D017398:Alternative Splicing / Q000187:drug effects / Q000502:physiology; D020816:Amino Acid Motifs; D006367:HeLa Cells; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D016899:Interferon-beta / Q000096:biosynthesis; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012367:RNA, Viral / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D007369:Interferon Inducers; D016328:NF-kappa B; D020033:Protein Isoforms; D012367:RNA, Viral; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D011070:Poly I-C