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Nat Immunol. 2015 Nov;16(11):1142-52. doi: 10.1038/ni.3268. Epub 2015 Sep 28.

Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity.

Author information

1
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
2
Department of Laboratory Medicine, the First Affiliated Hospital, Medical College of Xiamen University, Xiamen, China.
3
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.
4
Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
5
College of Medicine, Chang Gung University, Kwei-Shan, Taiwan.
6
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
7
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

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.

PMID:
26414765
PMCID:
PMC4618176
DOI:
10.1038/ni.3268
[Indexed for MEDLINE]
Free PMC Article

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