Pseudomonas aeruginosa ExoS Induces Intrinsic Apoptosis in Target Host Cells in a Manner That is Dependent on its GAP Domain Activity.
Pseudomonas aeruginosa ExoS Induces Intrinsic Apoptosis in Target Host Cells in a Manner That is Dependent on its GAP Domain Activity.
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DOI：
10.1038/s41598-018-32491-2
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发表时间：
2018-09-19
影响因子：
4.6
通讯作者：
Shafikhani SH
中科院分区：
文献类型：
--
作者：
Kaminski A;Gupta KH;Goldufsky JW;Lee HW;Gupta V;Shafikhani SH
铜绿假单胞菌是一种革兰氏阴性机会致病菌，可引起免疫功能低下的个体和囊性纤维化患者的严重感染。ExoS和ExoT是两种同源的双功能III型分泌系统（T3 SS）毒力因子，其在靶宿主细胞中诱导凋亡。它们在其N-末端具有GTdR活化蛋白（GAP）结构域，具有约76%的同源性，在其C-末端具有ADP-核糖基转移酶（ADPRT）结构域，靶向非重叠底物。差距和ADPRT结构域都有助于ExoT在靶上皮细胞中的细胞毒性，而据报道，ExoS诱导的细胞凋亡主要是由于其ADPRT结构域。在这份报告中，我们证明了ExoS/GAP结构域是诱导线粒体凋亡的必要和充分条件。我们的数据表明，与ExoS/GAP结构域中毒导致Bax和Bim富集到线粒体外膜，线粒体膜的破坏和细胞色素c释放到胞质溶胶中，其激活启动子半胱天冬酶-9和效应子半胱天冬酶-3，执行细胞死亡。我们认为，差距域在ExoS诱导的细胞凋亡中的贡献在以前的研究中被忽视，因为与ADPRT相比，GAP结构域的细胞毒性动力学较慢。我们的数据澄清了这一领域，并揭示了ExoS/GAP作为细胞凋亡诱导剂的新毒力功能。
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that causes serious infections in immunocompromised individuals and cystic fibrosis patients. ExoS and ExoT are two homologous bifunctional Type III Secretion System (T3SS) virulence factors that induce apoptosis in target host cells. They possess a GTPase Activating Protein (GAP) domain at their N-termini, which share ~76% homology, and an ADP-ribosyltransferase (ADPRT) domain at their C-termini, which target non-overlapping substrates. Both the GAP and the ADPRT domains contribute to ExoT’s cytotoxicity in target epithelial cells, whereas, ExoS-induced apoptosis is reported to be primarily due to its ADPRT domain. In this report, we demonstrate that ExoS/GAP domain is both necessary and sufficient to induce mitochondrial apoptosis. Our data demonstrate that intoxication with ExoS/GAP domain leads to enrichment of Bax and Bim into the mitochondrial outer-membrane, disruption of mitochondrial membrane and release of and cytochrome c into the cytosol, which activates initiator caspase-9 and effector caspase-3, that executes cellular death. We posit that the contribution of the GAP domain in ExoS-induced apoptosis was overlooked in prior studies due to its slower kinetics of cytotoxicity as compared to ADPRT. Our data clarify the field and reveal a novel virulence function for ExoS/GAP as an inducer of apoptosis.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1038/nrm3999
发表时间：
2015-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Fuchs Y;Steller H
通讯作者：
Steller H
影响因子：
32.4
作者：
Arsura, M;Wu, M;Sonenshein, GE
通讯作者：
Sonenshein, GE
影响因子：
4.8
作者：
Ganesan, AK;Frank, DW;Barbieri, JT
通讯作者：
Barbieri, JT
影响因子：
11.8
作者：
Furman, AC;Jacobs, J;Sepkowitz, KA
通讯作者：
Sepkowitz, KA