International Immunology Advance Access originally published online on June 28, 2004
International Immunology 2004 16(8):1143-1154; doi:10.1093/intimm/dxh115
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© 2004 The Japanese Society for Immunology
ORIGINAL RESEARCH PAPERS |
The cytoplasmic ‘linker region’ in Toll-like receptor 3 controls receptor localization and signaling
1 Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511, Japan
2 Department of Molecular Immunology, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan
3 Department of Cell Biology, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan
4 Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
Correspondence to: M. Matsumoto; E-mail: matumoto-mi{at}mc.pref.osaka.jp
Toll-like receptor 3 (TLR3) recognizes double-stranded RNA and transmits signals to activate NF-
B and the interferon (IFN)-ß promoter via the newly identified adaptor, TICAM-1. The extracellular LRR domain of TLR3 is engaged in the ligand recognition, while the intracellular TIR domain is crucial for the adaptor binding and signal transduction upon ligand stimulation. Here, we analyzed TLR3 localization in human monocyte-derived immature dendritic cells (iDCs) and stable transfectants expressing human TLR3 by immunofluorescence staining and confocal microscopy. TLR3 was predominantly localized in specific but as yet unidentified intracellular vesicles where TLR3 signaling was initiated. Expression analysis of TLR3-tail-truncated mutants revealed that the cytoplasmic ‘linker’ region (residues 730–755) determines the intracellular localization of TLR3. Site-directed mutagenesis of the linker region allowed us to identify the relevant determinants as Arg740 and Val741 residues for intracellular expression of TLR3. Furthermore, alanine scanning of the linker region demonstrated that the Phe732, Leu742 and Gly743 in the TLR3 cytoplasmic linker region are essential for ligand-induced NF-B and IFN-ß promoter activation. Thus, the cytoplasmic linker region of TLR3 regulates receptor retention inside the organelle and signaling, which may be closely linked to TLR3 function in DCs.
Keywords: dendritic cell, innate immunity, TLR adaptors, type I interferon, viral infection
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