Negative control of TLR3 signaling by TICAM1 down-regulation.
Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (TICAM1, also called TRIF) is an important adaptor protein in TLR3 and TLR4 signaling pathways that mediate proinflammatory cytokine and IFN responses. Negative regulation of TICAM1 by exogenous viral protease or by endogenous caspase and proteasome have been reported to shut down TICAM1-mediated signaling. In this study, we discovered that down-regulation of TICAM1, but not other components in this signaling pathway, occurred in a natural process of TLR3 activation induced by double-stranded RNA or human rhinovirus (RV) infection in airway epithelial cells and various other cell types. TICAM1 was essential for IFN expression, and the loss of TICAM1 significantly elevated RV production. The low level of TICAM1 protein expression, caused by the prior double-stranded RNA treatment, led to a lack of IFN production upon additional treatment, suggesting receptor desensitization. In follow-up studies, TICAM1 down-regulation was found to be dependent on TLR3 but not RIG1, MDA5, or PKR and appeared to be regulated post-translationally. Neither proteasome nor caspase inhibitors could prevent TICAM1 down-regulation. Instead, a lysosome-mediated process appeared to be involved, suggesting a novel mechanism that is different from previous reports. In conclusion, TICAM1 down-regulation is an essential step in TLR3 activation, and its function is to stop TLR3-mediated IFN production.
School of Public Health, China Medical University, Shenyang, China.
Shasha
S
Tao
Lingxiang
L
Zhu
Pakkei
P
Lee
Wai-ming
WM
Lee
Kenneth
K
Knox
Jie
J
Chen
Yuanpu Peter
YP
Di
Yin
Y
Chen
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D001483:Base Sequence; D017931:DNA Primers; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D007372:Interferons / Q000096:biosynthesis; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D017931:DNA Primers; D034741:RNA, Small Interfering; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D007372:Interferons