Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin
Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin
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DOI：
10.1016/j.cell.2007.04.043
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发表时间：
2007-07-13
期刊：
影响因子：
64.5
通讯作者：
Pieters, Jean
中科院分区：
文献类型：
--
作者：
Jayachandran, Rajesh;Sundaramurthy, Varadharajan;Pieters, Jean
病原性分枝杆菌通过避免溶酶体递送而在巨噬细胞内存活，而是驻留在分枝杆菌吞噬体中。在感染时，白细胞特异性蛋白冠蛋白1被主动募集到分枝杆菌吞噬体，在那里它通过未知的机制阻断溶酶体递送。对冠蛋白1缺陷小鼠巨噬细胞的分析表明，冠蛋白1是不依赖于事实的过程，如吞噬作用，运动性和膜皱褶。然而，在分枝杆菌感染时，冠蛋白1需要激活钙依赖性磷酸酶钙调神经磷酸酶，从而阻断分枝杆菌的溶酶体递送。在没有冠蛋白1的情况下，钙调磷酸酶活性不发生，导致溶酶体递送和杀死分枝杆菌。此外，用环孢菌素A或FK 506阻断钙调磷酸酶活化导致溶酶体递送和细胞内分枝杆菌杀灭。这些结果表明冠蛋白1在激活巨噬细胞中的Ca 2+依赖性信号传导过程中的作用，并揭示了钙调神经磷酸酶在分枝杆菌感染后调节吞噬体-溶酶体融合中的功能。
Pathogenic mycobacteria survive within macrophages by avoiding lysosomal delivery, instead residing in mycobacterial phagosomes. Upon infection, the leukocyte- specific protein coronin 1 is actively recruited to mycobacterial phagosomes, where it blocks lysosomal delivery by an unknown mechanism. Analysis of macrophages from coronin 1- deficient mice showed that coronin 1 is dispensable for Factindependent processes such as phagocytosis, motility, and membrane ruffling. However, upon mycobacterial infection, coronin 1 was required for activation of the Ca2+- dependent phosphatase calcineurin, thereby blocking lysosomal delivery of mycobacteria. In the absence of coronin 1, calcineurin activity did not occur, resulting in lysosomal delivery and killing of mycobacteria. Furthermore, blocking calcineurin activation with cyclosporin A or FK506 led to lysosomal delivery and intracellular mycobacterial killing. These results demonstrate a role for coronin 1 in activating Ca2+ dependent signaling processes in macrophages and reveal a function for calcineurin in the regulation of phagosome- lysosome fusion upon mycobacterial infection.