Funami Kenji, Matsumoto Misako, Oshiumi Hiroyuki, Inagaki Fuyuhiko, Seya Tsukasa
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Biochem Soc Trans. 2017 Aug 15;45(4):929-935. doi: 10.1042/BST20160259. Epub 2017 Jun 19.
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.
Toll样受体4（TLR4）识别脂多糖（LPS），产生促炎细胞因子和I型干扰素，并与内毒素休克的触发因素相关。TLR4通过其Toll样白细胞介素-1受体同源（TIR）结构域与含TIR结构域的接头分子-2（TICAM-2）/TRAM[含TIR结构域的接头诱导干扰素-β（TRIF）相关接头分子]相互作用。TICAM-2作为一种支架蛋白，激活含TIR结构域的接头分子-1（TICAM-1）/TRIF。根据核磁共振的结构分析，TICAM-2通过酸性氨基酸基序E87/D88/D89与TICAM-1相互作用。TICAM-2的TIR结构域与膜下TLR4的TIR结构域二聚体结合，并且TICAM-2自身也形成二聚体并构成与TICAM-1的结合位点。TICAM-2在内体中的定位对于TLR4介导的来自内体的I型干扰素诱导信号至关重要。N端肉豆蔻酰化使TICAM-2锚定在内体膜上。此外，我们已经确定了两个酸性氨基酸D91/E92作为协同决定TICAM-2内体定位的功能基序。TICAM-2的这种结构信息表明，特定结构对于TICAM-2的内体定位和I型干扰素产生是不可或缺的。结合关于LPS的细胞质传感器的知识，TICAM-2/TICAM-1可能符合TLR4上的信号网络，以促进细胞因子紊乱的诱导。
