Visintin Alberto, Latz Eicke, Monks Brian G, Espevik Terje, Golenbock Douglas T
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
J Biol Chem. 2003 Nov 28;278(48):48313-20. doi: 10.1074/jbc.M306802200. Epub 2003 Sep 5.
Three cell-surface proteins have been recognized as components of the mammalian signaling receptor for bacterial lipopolysaccharide (LPS): CD14, Toll-like receptor-4 (TLR4), and MD-2. Biochemical and visual studies shown here demonstrate that the role of CD14 in signal transduction is to enhance LPS binding to MD-2, although its expression is not essential for cellular activation. These studies clarify how MD-2 functions: we found that MD-2 enables TLR4 binding to LPS and allows the formation of stable receptor complexes. MD-2 must be bound to TLR4 on the cell surface before binding can occur. Consequently, TLR4 clusters into receptosomes (many of which are massive) that recruit intracellular toll/IL-1/resistance domain-containing adapter proteins within minutes, thus initiating signal transduction. TLR4 activation correlates with the ability of MD-2 to bind LPS, as MD-2 mutants that still bind TLR4, but are impaired in the ability to bind LPS, conferred a greatly blunted LPS response. These findings help clarify the earliest events of TLR4 triggering by LPS and identify MD-2 as an attractive target for pharmacological intervention in endotoxin-mediated diseases.
三种细胞表面蛋白已被确认为哺乳动物细菌脂多糖（LPS）信号受体的组成部分：CD14、Toll样受体4（TLR4）和MD-2。本文所示的生化和可视化研究表明，CD14在信号转导中的作用是增强LPS与MD-2的结合，尽管其表达对于细胞激活并非必不可少。这些研究阐明了MD-2的功能：我们发现MD-2能使TLR4与LPS结合，并允许形成稳定的受体复合物。MD-2必须在细胞表面与TLR4结合后才能发生结合。因此，TLR4聚集到受体小体中（其中许多很大），在几分钟内招募含细胞内toll/IL-1/抗性结构域的衔接蛋白，从而启动信号转导。TLR4激活与MD-2结合LPS的能力相关，因为仍能结合TLR4但结合LPS能力受损的MD-2突变体导致LPS反应大大减弱。这些发现有助于阐明LPS触发TLR4的最早事件，并确定MD-2是内毒素介导疾病药理干预的一个有吸引力的靶点。
