Kinases mst1 and mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity
Open accessAbstract
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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MST1/2-deficient BMDM show reduced ROS production into phagosomes and increased bacterial burden during L.m. infection.
“MST1/2-deficient BMDM showed reduced ROS production into phagosomes and increased bacterial burden.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [246]
ROS production either from Nox2 or from mitochondria are crucial players for antilisterial defense.
“These studies show that ROS production either from Nox2 or from mitochondria are crucial players for antilisterial defense (Figure 5).”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [246]
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References 50 · Cited by 264
- Authors
- 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., Johnson, R. L., Chien, K.-Y., Lin, S.-C., Han, J., Avruch, J., Chen, L., & Zhou, D.
- Affiliations
- Xiamen University (CN)
- University of Science and Technology of China (CN)
- The University of Texas MD Anderson Cancer Center (US)
- Chang Gung University (TW)
- Harvard University (US)
- Corresponding author
- Chen, Lanfen
- Zhou, Dawang
- ORCID
- Venue
- Nature Immunology
- Published
- 2015-09-28
- Volume
- 16
- Issue
- 11
- Pages
- 1142-1152
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4618176
- OpenAlex
- W1814713647
- Cited by
- 264
- References
- 50
- Citations by year
- 2026: 17 · 2025: 13 · 2024: 32 · 2023: 23 · 2022: 26 · 2021: 36 · 2020: 33 · 2019: 31 · 2018: 20 · 2017: 20 · 2016: 11 · 2015: 2
- FWCI
- 8.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01CA136567, P30CA016672)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- MST1, MST2, MEK, reactive oxygen species, mitochondrial trafficking, Rac GTPase, TRAF6, ECSIT, Toll-like receptor signaling, phagocytosis, bactericidal activity, innate immunity, bacterial infection susceptibility
- MeSH terms
- Serine-Threonine Kinase 3, Hippo Kinases, Animals, Bacterial Infections, Blood Bactericidal Activity, Cell Line, Humans, Mice, Inbred C57BL, Mitochondria, Phagocytes, Phagosomes, Signal Transduction, Minor Histocompatibility Antigens, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Mice, Knockout, Sepsis, rac GTP-Binding Proteins, TNF Receptor-Associated Factor 6, Adaptor Proteins, Signal Transducing, Toll-Like Receptors, Mice, Protein Kinase C-alpha, Ubiquitination, rho Guanine Nucleotide Dissociation Inhibitor beta
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