Joshi Shilpa A, Ball David A, Sun Mei G, Carlsson Fredric, Watkins Brigitte Y, Aggarwal Nina, McCracken Jenna M, Huynh Kassidy K, Brown Eric J
Department of Microbial Pathogenesis, Genentech, South San Francisco, CA 94080, USA.
Chem Biol. 2012 Mar 23;19(3):372-80. doi: 10.1016/j.chembiol.2012.01.008.
Pathogenic mycobacteria, which cause multiple diseases including tuberculosis, secrete factors essential for disease via the ESX-1 protein export system and are partially protected from host defenses by their lipid-rich cell envelopes. These pathogenic features of mycobacterial biology are believed to act independently of each other. Key ESX-1 components include three ATPases, and EccA1 (Mycobacterium marinum MMAR_5443; M. tuberculosis Rv3868) is the least characterized. Here we show that M. marinum EccA1's ATPase activity is required for ESX-1-mediated protein secretion, and surprisingly for the optimal synthesis of mycolic acids, integral cell-envelope lipids. Increased mycolic acid synthesis defects, observed when an EccA1-ATPase mutant is expressed in an eccA1-null strain, correlate with decreased in vivo virulence and intracellular growth. These data suggest that two mycobacterial virulence hallmarks, ESX-1-dependent protein secretion and mycolic acid synthesis, are critically linked via EccA1.
致病性分枝杆菌可引发包括结核病在内的多种疾病，它通过ESX-1蛋白输出系统分泌致病所需的因子，其富含脂质的细胞壁可部分抵御宿主防御。分枝杆菌生物学的这些致病特性被认为是相互独立起作用的。ESX-1的关键组成部分包括三种ATP酶，而EccA1（海分枝杆菌MMAR_5443；结核分枝杆菌Rv3868）的特征了解最少。我们在此表明，海分枝杆菌EccA1的ATP酶活性是ESX-1介导的蛋白分泌所必需的，而且令人惊讶的是，对于细胞壁完整脂质——分枝菌酸的最佳合成也是必需的。当在eccA1基因缺失菌株中表达EccA1-ATP酶突变体时，观察到分枝菌酸合成缺陷增加，这与体内毒力降低和细胞内生长减少相关。这些数据表明，分枝杆菌的两个致病标志，即ESX-1依赖性蛋白分泌和分枝菌酸合成，通过EccA1紧密相连。
