title: Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity.
abstract: Mitochondria need to be juxtaposed to phagosomes for the synergistic production of ample reactive oxygen species (ROS) in phagocytes to kill pathogens. However, how phagosomes transmit signals to recruit mitochondria has remained unclear. Here we found that the kinases Mst1 and Mst2 functioned to control ROS production by regulating mitochondrial trafficking and mitochondrion-phagosome juxtaposition. Mst1 and Mst2 activated the GTPase Rac to promote Toll-like receptor (TLR)-triggered assembly of the TRAF6-ECSIT complex that is required for the recruitment of mitochondria to phagosomes. Inactive forms of Rac, including the human Rac2(D57N) mutant, disrupted the TRAF6-ECSIT complex by sequestering TRAF6 and substantially diminished ROS production and enhanced susceptibility to bacterial infection. Our findings demonstrate that the TLR-Mst1-Mst2-Rac signaling axis is critical for effective phagosome-mitochondrion function and bactericidal activity.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Shihao
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Hongtan
authors.initials: H
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Hong
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Changchuan
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Laboratory Medicine, the First Affiliated Hospital, Medical College of Xiamen University, Xiamen, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Qingxu
authors.initials: Q
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Mingting
authors.initials: M
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Jinjia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Siyang
authors.initials: S
authors.lastname: Song
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Hong-Rui
authors.initials: HR
authors.lastname: Wang
authors.affiliation: Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.
authors.forename: Rongbin
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: College of Medicine, Chang Gung University, Kwei-Shan, Taiwan.
authors.forename: Kun-Yi
authors.initials: KY
authors.lastname: Chien
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Avruch
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Lanfen
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Dawang
authors.initials: D
authors.lastname: Zhou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001424:Bacterial Infections / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D001770:Blood Bactericidal Activity / Q000276:immunology; D002460:Cell Line; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D010586:Phagocytes / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051571:Protein Kinase C-alpha / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018805:Sepsis / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors / Q000378:metabolism; D054875:Ubiquitination; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015778:Minor Histocompatibility Antigens; D051571:Protein Kinase C-alpha; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D000090742:Serine-Threonine Kinase 3; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D020744:rac GTP-Binding Proteins; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; C569659:Arhgdib protein, mouse; C558806:ECSIT protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C490818:Stk3 protein, mouse