Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity.
Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity.
复制标题
激酶 Mst1 和 Mst2 正向调节活性氧的吞噬诱导和杀菌活性。
DOI：
10.1038/ni.3268
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发表时间：
2015-11
影响因子：
30.5
通讯作者：
Zhou D
中科院分区：
文献类型：
--
作者：
Geng J;Sun X;Wang P;Zhang S;Wang X;Wu H;Hong L;Xie C;Li X;Zhao H;Liu Q;Jiang M;Chen Q;Zhang J;Li Y;Song S;Wang HR;Zhou R;Johnson RL;Chien KY;Lin SC;Han J;Avruch J;Chen L;Zhou D
线粒体需要与吞噬体并列，以协同产生充足的活性氧（ROS）在吞噬细胞中杀死病原体。然而，吞噬体如何传递信号以招募线粒体仍不清楚。在这里，我们报道了Mst1和Mst2激酶通过调节线粒体运输和线粒体-吞噬体并并来控制ROS的产生。Mst1和Mst2激活Rac GTPase，促进toll样受体（TLR）触发的TRAF6-ECSIT复合物的组装，这是线粒体招募到吞噬体所必需的。Rac的失活形式，包括人类Rac2D57N突变体，通过隔离TRAF6破坏TRAF6- ecsit复合物，严重抑制ROS的产生，并大大增加对细菌感染的易感性。这些发现表明，TLR-Mst1-Mst2-Rac信号轴对有效的吞噬体-线粒体功能和杀菌活性至关重要。
Mitochondria need to be juxtaposted to phagosomes to synergistically produce ample reactive oxygen species (ROS) in phagocytes for pathogens killing. However, how phagosomes transmit signal to recruit mitochondria remains unclear. Here, we report that the kinases Mst1 and Mst2 function to control ROS production by regulating mitochondrial trafficking and mitochondrion-phagosome juxtaposition. Mst1 and Mst2 activate Rac GTPase to promote Toll-like receptor (TLR)-triggered assembly of the TRAF6-ECSIT complex that is required for mitochondrial recruitment to phagosomes. Inactive forms of Rac, including the human Rac2D57N mutant, disrupt the TRAF6-ECSIT complex by sequestering TRAF6, and severely dampen ROS production and greatly increase susceptibility to bacterial infection. These findings demonstrate the TLR-Mst1-Mst2-Rac signalling axis to be critical for effective phagosome-mitochondrion function and bactericidal activity.