Mycolyltransferase-mediated Glycolipid Exchange in Mycobacteria
Mycolyltransferase-mediated Glycolipid Exchange in Mycobacteria
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DOI：
10.1074/jbc.m805776200
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发表时间：
2008-10-24
影响因子：
4.8
通讯作者：
Sugita, Masahiko
中科院分区：
文献类型：
--
作者：
Matsunaga, Isamu;Naka, Takashi;Sugita, Masahiko
海藻糖二霉菌酸酯（TDM），也称为索因子，是分枝杆菌细胞壁的主要表面糖脂。由于其在感染、佐剂和免疫治疗模型中具有强大的生物学功能，因此确定其生物合成的调控方式非常重要。在这里，我们发现葡萄糖是一种在环境中不容易获得的宿主衍生产物，它会导致鸟分枝杆菌下调 TDM 表达，同时上调另一种在 T 细胞激活中具有免疫作用的主要糖脂——葡萄糖单分枝菌酯 (GMM) 的产生。在体外，TDM 和 GMM 相互调节的机制涉及抗原 85A 的竞争性底物选择。从 TDM 生物合成到 GMM 生物合成的转变发生在哺乳动物宿主体内葡萄糖的生理浓度附近。我们进一步证明 GMM 是由小鼠肺部生长的分枝杆菌体内产生的。这些结果建立了 GMM 生产的酶促途径。更一般地说，这些观察结果提供了一种特定的酶机制，用于响应从非细胞生长环境到细胞生长环境的转变而动态改变细胞壁糖脂重塑，包括宿主免疫系统监测的因素。
Trehalose dimycolate (TDM), also known as cord factor, is a major surface glycolipid of the cell wall of mycobacteria. Because of its potent biological functions in models of infection, adjuvancy, and immunotherapy, it is important to determine how its biosynthesis is regulated. Here we show that glucose, a host-derived product that is not readily available in the environment, causes Mycobacterium avium to down-regulate TDM expression while up-regulating production of another major glycolipid with immunological roles in T cell activation, glucose monomycolate (GMM). In vitro, the mechanism of reciprocal regulation of TDM and GMM involves competitive substrate selection by antigen 85A. The switch from TDM to GMM biosynthesis occurs near the physiological concentration of glucose present in mammalian hosts. We further demonstrate that GMM is produced in vivo by mycobacteria growing in mouse lung. These results establish an enzymatic pathway for GMM production. More generally, these observations provide a specific enzymatic mechanism for dynamic alterations of cell wall glycolipid remodeling in response to the transition from noncellular to cellular growth environments, including factors that are monitored by the host immune system.