A cardinal role for cathepsin d in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci.
A cardinal role for cathepsin d in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci.
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DOI：
10.1371/journal.ppat.1001262
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发表时间：
2011-01-27
期刊：
影响因子：
6.7
通讯作者：
Dockrell DH
中科院分区：
文献类型：
--
作者：
Bewley MA;Marriott HM;Tulone C;Francis SE;Mitchell TJ;Read RC;Chain B;Kroemer G;Whyte MK;Dockrell DH
巨噬细胞对肺炎球菌的杀菌功能通过它们的凋亡死亡而增强，其由抗凋亡蛋白Mcl-1控制。在这里，我们表明，溶酶体膜透化（LMP）和细胞溶质易位的激活组织蛋白酶D发生前激活的线粒体途径的巨噬细胞凋亡。在肺炎球菌感染期间，药理学抑制或敲除组织蛋白酶D阻断巨噬细胞凋亡。由于组织蛋白酶D激活，Mcl-1与其泛素连接酶Mule相互作用，表达下降。抑制组织蛋白酶D对早期细菌杀灭没有影响，但抑制了体外肺炎球菌的溶血相关杀灭的晚期阶段。携带组织蛋白酶D−/−造血系统的小鼠表现出体内巨噬细胞凋亡减少，肺炎球菌清除减少，中性粒细胞募集增加，以控制肺部感染。这些发现确立了组织蛋白酶D介导的溶酶体凋亡途径在肺宿主防御中的意外作用，并强调了肺结核相关微生物杀伤对巨噬细胞功能的重要性。组织巨噬细胞在持续摄入和杀死细菌后经常经历称为细胞凋亡的细胞死亡程序。在巨噬细胞中，当巨噬细胞的初始杀伤能力耗尽时，诱导凋亡增强细菌杀伤。我们已经研究了巨噬细胞暴露于肺炎球菌（细菌性肺炎的最常见原因）的凋亡机制。我们发现，细胞结构含有摄入的细菌，吞噬溶酶体，成为透化早期死亡过程中。肺炎球菌暴露激活吞噬溶酶体酶，组织蛋白酶D，诱导细胞凋亡。组织蛋白酶D的激活是线粒体透化所必需的，线粒体是一种参与细胞凋亡诱导的细胞器。组织蛋白酶D通过增强其与介导其降解的酶的关联来降低巨噬细胞中细胞凋亡的负调节因子Mcl-1的水平。这些发现的重要性在骨髓移植模型中得到了证实，在该模型中，小鼠接受了来自含有或缺乏组织蛋白酶D基因的小鼠的骨髓。该模型表明，当组织蛋白酶D缺乏时，肺泡巨噬细胞的凋亡减少，并且这损害了小鼠肺中肺炎球菌的清除。我们的结论是，在细菌的挑战，溶酶体透化和组织蛋白酶D激活触发一个新的死亡途径，在及时的方式，连接细菌杀死细胞凋亡诱导。
The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D−/− hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function. Tissue macrophages frequently undergo a program of cell death, termed apoptosis, following sustained ingestion and killing of bacteria. In macrophages, induction of apoptosis enhances bacterial killing when macrophages' initial killing capacity is exhausted. We have investigated the mechanism of apoptosis in macrophages exposed to pneumococci, the commonest cause of bacterial pneumonia. We show that the cell structure containing ingested bacteria, the phagolysosome, becomes permeabilized early in the death process. Pneumococcal exposure activates a phagolysosomal enzyme, cathepsin D, which induces apoptosis. Cathepsin D activation is required for permeabilization of mitochondria, an organelle implicated in apoptosis induction. Cathepsin D reduces levels of a negative regulator of apoptosis in macrophages, Mcl-1, by enhancing its association with an enzyme, which mediates its degradation. The importance of these findings was confirmed in a bone marrow transplant model in which mice either received bone marrow from mice containing or lacking the cathepsin D gene. This model showed that reduced apoptosis of alveolar macrophages occurred when cathepsin D was lacking, and that this impaired clearance of pneumococci in the mouse lung. We conclude that during bacterial challenge, lysosomal permeabilization and cathepsin D activation triggers a novel death pathway, in a timely fashion, linking bacterial killing to apoptosis induction.
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影响因子：
3.2
作者：
Free, P;Hurley, CA;Tabor, AB
通讯作者：
Tabor, AB
影响因子：
9.6
作者：
de Roux, AD;Marco, MA;Torres, A
通讯作者：
Torres, A
影响因子：
4.8
作者：
Bidère, N;Lorenzo, HK;Senik, A
通讯作者：
Senik, A
影响因子：
6.4
作者：
Ali, F;Lee, ME;Dockrell, DH
通讯作者：
Dockrell, DH
DOI：
10.1083/jcb.104.2.253
发表时间：
1987-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Capony F;Morisset M;Barrett AJ;Capony JP;Broquet P;Vignon F;Chambon M;Louisot P;Rochefort H
通讯作者：
Rochefort H