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

Jing Geng; Xiufeng Sun; Ping Wang; Shihao Zhang; Xiaozhen Wang; Hongtan Wu; Lixin Hong; Changchuan Xie; Xun Li; Hao Zhao; Qingxu Liu; Mingting Jiang; Qinghua Chen; Jinjia Zhang; Yang Li; Siyang Song; Hong Rui Wang; Rongbin Zhou; Randy L. Johnso; Kun Yi Chien; Sheng Cai Lin; Jiahuai Han; Joseph Avruch; Lanfen Chen; Dawang Zhou

doi:10.1038/ni.3268

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

Jing Geng, Xiufeng Sun, Ping Wang, Shihao Zhang, Xiaozhen Wang, Hongtan Wu, Lixin Hong, Changchuan Xie, Xun Li, Hao Zhao, Qingxu Liu, Mingting Jiang, Qinghua Chen, Jinjia Zhang, Yang Li, Siyang Song, Hong Rui Wang, Rongbin Zhou, Randy L. Johnso, Kun Yi ChienSheng Cai Lin, Jiahuai Han, Joseph Avruch, Lanfen Chen^*, Dawang Zhou

^*Corresponding author for this work

Department of Biochemistry

Research output: Contribution to journal › Journal Article › peer-review

221 Scopus citations

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.

Original language	English
Pages (from-to)	1142-1152
Number of pages	11
Journal	Nature Immunology
Volume	16
Issue number	11
DOIs	https://doi.org/10.1038/ni.3268
State	Published - 20 10 2015

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Publisher Copyright:
© 2015 Nature America, Inc.

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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, H. R., Zhou, R., Johnso, R. L., ... Zhou, D. (2015). Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nature Immunology, 16(11), 1142-1152. https://doi.org/10.1038/ni.3268

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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.",

author = "Jing Geng and Xiufeng Sun and Ping Wang and Shihao Zhang and Xiaozhen Wang and Hongtan Wu and Lixin Hong and Changchuan Xie and Xun Li and Hao Zhao and Qingxu Liu and Mingting Jiang and Qinghua Chen and Jinjia Zhang and Yang Li and Siyang Song and Wang, \{Hong Rui\} and Rongbin Zhou and Johnso, \{Randy L.\} and Chien, \{Kun Yi\} and Lin, \{Sheng Cai\} and Jiahuai Han and Joseph Avruch and Lanfen Chen and Dawang Zhou",

note = "Publisher Copyright: {\textcopyright} 2015 Nature America, Inc.",

year = "2015",

month = oct,

day = "20",

doi = "10.1038/ni.3268",

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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, Johnso, RL, Chien, KY, Lin, SC, Han, J, Avruch, J, Chen, L & Zhou, D 2015, 'Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity', Nature Immunology, vol. 16, no. 11, pp. 1142-1152. https://doi.org/10.1038/ni.3268

TY - JOUR

T1 - Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity

AU - Geng, Jing

AU - Sun, Xiufeng

AU - Wang, Ping

AU - Zhang, Shihao

AU - Wang, Xiaozhen

AU - Wu, Hongtan

AU - Hong, Lixin

AU - Xie, Changchuan

AU - Li, Xun

AU - Zhao, Hao

AU - Liu, Qingxu

AU - Jiang, Mingting

AU - Chen, Qinghua

AU - Zhang, Jinjia

AU - Li, Yang

AU - Song, Siyang

AU - Wang, Hong Rui

AU - Zhou, Rongbin

AU - Johnso, Randy L.

AU - Chien, Kun Yi

AU - Lin, Sheng Cai

AU - Han, Jiahuai

AU - Avruch, Joseph

AU - Chen, Lanfen

AU - Zhou, Dawang

PY - 2015/10/20

Y1 - 2015/10/20

N2 - 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.

AB - 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.

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M3 - 文章

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AN - SCOPUS:84944897402

SN - 1529-2908

VL - 16

SP - 1142

EP - 1152

JO - Nature Immunology

JF - Nature Immunology

IS - 11

ER -

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

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