Regulation of Mycobacterium tuberculosis cell envelope composition and virulence by intramembrane proteolysis
Regulation of Mycobacterium tuberculosis cell envelope composition and virulence by intramembrane proteolysis
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DOI：
10.1038/nature03713
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发表时间：
2005-07-21
期刊：
影响因子：
64.8
通讯作者：
Glickman, MS
中科院分区：
文献类型：
--
作者：
Makinoshima, H;Glickman, MS
结核分枝杆菌感染是一场持续的全球健康危机，每年导致 200 万人死亡(1)。尽管结核分枝杆菌细胞包膜的结构不同的脂质各自在毒力或持久性方面具有非冗余的作用(2-7)，但调节结核分枝杆菌细胞包膜组成的分子机制尚不清楚。在高等真核生物中，膜组成由位点二蛋白酶 (S2P) 介导的甾醇调节元件结合蛋白 (8,9)（控制脂质生物合成的膜结合转录因子）的裂解控制。 S2P 是广泛分布的膜金属蛋白酶家族的创始成员 (10,11)，可在跨膜片段内切割底物蛋白 (12)。在这里，我们展示了以前未表征的结核分枝杆菌S2P同源物（Rv2869c）调节结核分枝杆菌细胞包膜组成、体内生长和体内持久性。这些结果证实，受调节的膜内蛋白水解是原核生物中控制膜组成的保守机制，并表明这种蛋白水解是结核分枝杆菌中细胞包膜毒力决定因素的近端调节剂。
Mycobacterium tuberculosis infection is a continuing global health crisis that kills 2 million people each year(1). Although the structurally diverse lipids of the M. tuberculosis cell envelope each have non-redundant roles in virulence or persistence(2-7), the molecular mechanisms regulating cell envelope composition in M. tuberculosis are undefined. In higher eukaryotes, membrane composition is controlled by site two protease (S2P)-mediated cleavage of sterol regulatory element binding proteins(8,9), membrane-bound transcription factors that control lipid biosynthesis. S2P is the founding member of a widely distributed family of membrane metalloproteases(10,11) that cleave substrate proteins within transmembrane segments(12). Here we show that a previously uncharacterized M. tuberculosis S2P homologue (Rv2869c) regulates M. tuberculosis cell envelope composition, growth in vivo and persistence in vivo. These results establish that regulated intramembrane proteolysis is a conserved mechanism controlling membrane composition in prokaryotes and show that this proteolysis is a proximal regulator of cell envelope virulence determinants in M. tuberculosis.