Novel Roles of Lysines 122, 125, and 58 in Functional Differences between Human and Murine MD-21
Novel Roles of Lysines 122, 125, and 58 in Functional Differences between Human and Murine MD-21
复制标题
赖氨酸 122、125 和 58 在人和鼠 MD-21 功能差异中的新作用
作者：
Jožica Vašl;A. Oblak;T. Gioannini;J. Weiss;R. Jerala
MD-2/TLR 4复合物为哺乳动物先天免疫对革兰氏阴性细菌内毒素的识别和应答提供了高度稳健的机制。尽管总体上结构和功能相似，但人（h）和鼠（m）MD-2显示出几种物种相关的差异，包括hMD-2而不是mMD-2在不存在TLR 4的情况下结合内毒素（E）的能力。只有当mMD-2和mTLR 4在同一细胞中共表达时，野生型mMD-2才能支持E对TLR 4依赖性细胞的激活。然而，用hMD-2的相应残基（赖氨酸）替换mMD-2的Glu 122、Leu 125和/或Asn 58足以产生可溶性细胞外MD-2，其与单体E ·sCD 14复合物反应以形成细胞外单体E · MD-2，其活化表达TLR 4而不含MD-2的细胞。此外，与野生型mMD-2相反，双重和三重mMD-2突变体也支持与人TLR 4组合的E触发信号传导。相反，hMD-2的K125 L突变体仅在与TLR 4共表达时才与E ·CD 14反应并激活TLR 4，而在无TLR 4的情况下分泌时则不反应。这些发现揭示了赖氨酸122、125和58在人MD-2中的新作用，其有助于人和鼠MD-2之间的功能差异，并且可能导致人和小鼠对内毒素的敏感性差异。
The MD-2/TLR4 complex provides a highly robust mechanism for recognition and response of mammalian innate immunity to Gram-negative bacterial endotoxins. Despite overall close structural and functional similarity, human (h) and murine (m) MD-2 show several species-related differences, including the ability of hMD-2, but not mMD-2, to bind endotoxin (E) in the absence of TLR4. Wild-type mMD-2 can support TLR4-dependent cell activation by E only when mMD-2 and mTLR4 are coexpressed in the same cell. However, replacement of Glu122, Leu125, and/or Asn58 of mMD-2 with the corresponding residues (lysines) of hMD-2 was sufficient to yield soluble extracellular MD-2 that reacted with monomeric E · sCD14 complex to form extracellular monomeric E · MD-2 that activated cells expressing TLR4 without MD-2. Moreover, in contrast to wild-type mMD-2, double and triple mMD-2 mutants also supported E-triggered signaling in combination with human TLR4. Conversely, a K125L mutant of hMD-2 reacted with E · CD14 and activated TLR4 only when coexpressed with TLR4, and not when secreted without TLR4. These findings reveal novel roles of lysines 122, 125, and 58 in human MD-2 that contribute to the functional differences between human and murine MD-2 and, potentially, to differences in the sensitivity of humans and mice to endotoxin.
影响因子：
56.9
作者：
WRIGHT, SD;RAMOS, RA;MATHISON, JC
通讯作者：
MATHISON, JC
DOI：
10.1074/jbc.m105228200
发表时间：
2001-10
期刊：
Journal of endotoxin research
影响因子：
--
作者：
S. Viriyakosol;Peter S. Tobias;R. Kitchens;T. Kirkland
通讯作者：
S. Viriyakosol;Peter S. Tobias;R. Kitchens;T. Kirkland