Oshiumi Hiroyuki, Sasai Miwa, Shida Kyoko, Fujita Takashi, Matsumoto Misako, Seya Tsukasa
Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511, Japan.
J Biol Chem. 2003 Dec 12;278(50):49751-62. doi: 10.1074/jbc.M305820200. Epub 2003 Sep 30.
Lipopolysaccharide (LPS) is an agonist for Toll-like receptor (TLR) 4 and expresses many genes including NF-kappaB- and interferon regulatory factor (IRF)-3/IFN-inducible genes in macrophages and dendritic cells (DCs). TICAM-1/TRIF was identified as an adapter that facilitates activation of IRF-3 followed by expression of interferon (IFN)-beta genes in TLR3 signaling, but TICAM-1 does not directly bind TLR4. Although MyD88 and Mal/TIRAP adapters functions downstream of TLR4, DC maturation and IFN-beta induction are independent of MyD88 and Mal/TIRAP. In this investigation, we report the identification of a novel adapter, TICAM-2, that physically bridges TLR4 and TICAM-1 and functionally transmits LPS-TLR4 signaling to TICAM-1, which in turn activates IRF-3. In its structural features, TICAM-2 resembled Mal/TIRAP, an adapter that links TLR2/4 and MyD88. However, TICAM-2 per se exhibited minimal ability to activate NF-kappaB and the IFN-beta promoter. Hence, in LPS signaling TLR4 recruits two types of adapters, TIRAP and TICAM-2, to its cytoplasmic domain that are indirectly connected to two effective adapters, MyD88 and TICAM-1, respectively. We conclude that for LPS-TLR4-mediated activation of IFN-beta, the adapter complex of TICAM-2 and TICAM-1 plays a crucial role. This results in the construction of MyD88-dependent and -independent pathways separately downstream of the two distinct adapters.
脂多糖（LPS）是Toll样受体（TLR）4的激动剂，可在巨噬细胞和树突状细胞（DC）中表达包括NF-κB和干扰素调节因子（IRF）-3/IFN诱导基因在内的许多基因。TICAM-1/TRIF被鉴定为一种衔接蛋白，可促进IRF-3的激活，随后在TLR3信号传导中表达干扰素（IFN）-β基因，但TICAM-1不直接结合TLR4。尽管MyD88和Mal/TIRAP衔接蛋白在TLR4下游发挥作用，但DC的成熟和IFN-β的诱导与MyD88和Mal/TIRAP无关。在本研究中，我们报告了一种新型衔接蛋白TICAM-2的鉴定，它在物理上连接TLR4和TICAM-1，并在功能上将LPS-TLR4信号传递给TICAM-1，进而激活IRF-3。在结构特征上，TICAM-2类似于Mal/TIRAP，后者是一种连接TLR2/4和MyD88的衔接蛋白。然而，TICAM-2本身激活NF-κB和IFN-β启动子的能力很弱。因此，在LPS信号传导中，TLR4在其胞质结构域募集了两种衔接蛋白TIRAP和TICAM-2，它们分别间接连接到两种有效的衔接蛋白MyD88和TICAM-1。我们得出结论，对于LPS-TLR4介导的IFN-β激活，TICAM-2和TICAM-1的衔接蛋白复合物起着关键作用。这导致在两个不同衔接蛋白的下游分别构建了MyD88依赖性和非依赖性途径。
