Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS), produces pro-inflammatory cytokines and type I interferons, and associates with a trigger of endotoxin shock. TLR4 is interacted with a TIR domain-containing adaptor molecule-2 (TICAM-2)/TRAM [TRIF (TIR domain-containing adaptor-inducing interferon-β)-related adaptor molecule] via its Toll–interleukin-1 receptor homology (TIR) domain. TICAM-2 acts as a scaffold protein and activates TIR domain-containing adaptor molecule-1 (TICAM-1)/TRIF. According to the structural analysis by NMR, TICAM-2 interacts with TICAM-1 by the acidic amino acids motif, E87/D88/D89. The TIR domain of TICAM-2 couples with the dimer of TIR domain of TLR4 beneath the membrane, and TICAM-2 itself also forms dimer and constitutes a binding site with TICAM-1. Endosomal localization of TICAM-2 is essential for TLR4-mediated type I interferon-inducing signal from the endosome. N-terminal myristoylation allows TICAM-2 to anchor to the endosomal membrane. Additionally, we have identified two acidic amino acids, D91/E92, as a functional motif that cooperatively determines endosomal localization of TICAM-2. This structural information of TICAM-2 suggests that the specific structure is indispensable for the endosomal localization and type I interferon production of TICAM-2. Taken together with the knowledge on cytoplasmic sensors for LPS, TICAM-2/TICAM-1 may conform to a signal network on TLR4 to facilitate induction of cytokine disorders.
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August 2017
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Activating and inhibitory long non-coding RNAs of the NF-κβ canonical pathway. In this issue, Magagula et al. explore the lncRNAs that are directly involved in regulating innate immunity at various branches of the NF-κβ pathway, and also consider their potential diagnostic and therapeutic significance. For further details, see pages 953–962
Review Article|
June 16 2017
Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling
Kenji Funami;
1Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
Correspondence: Kenji Funami (kfunami@med.hokudai.ac.jp) or Tsukasa Seya (seya-tu@pop.med.hokudai.ac.jp)
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Misako Matsumoto;
Misako Matsumoto
1Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
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Hiroyuki Oshiumi;
Hiroyuki Oshiumi
1Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
2Department of Immunology, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan
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Fuyuhiko Inagaki;
Fuyuhiko Inagaki
*
3Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, N-21, W-11, Kita-ku, Sapporo 001-0021, Japan
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Tsukasa Seya
1Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
Correspondence: Kenji Funami (kfunami@med.hokudai.ac.jp) or Tsukasa Seya (seya-tu@pop.med.hokudai.ac.jp)
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Publisher: Portland Press Ltd
Received:
December 25 2016
Revision Received:
April 23 2017
Accepted:
May 02 2017
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2017
Biochem Soc Trans (2017) 45 (4): 929–935.
Article history
Received:
December 25 2016
Revision Received:
April 23 2017
Accepted:
May 02 2017
Citation
Kenji Funami, Misako Matsumoto, Hiroyuki Oshiumi, Fuyuhiko Inagaki, Tsukasa Seya; Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling. Biochem Soc Trans 15 August 2017; 45 (4): 929–935. doi: https://doi.org/10.1042/BST20160259
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