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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Bacterial Infections / etiology
  • Bacterial Infections / immunology
  • Bacterial Infections / metabolism
  • Blood Bactericidal Activity / immunology
  • Cell Line
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Minor Histocompatibility Antigens
  • Mitochondria / immunology
  • Mitochondria / metabolism
  • Mitochondria / microbiology
  • Phagocytes / immunology*
  • Phagocytes / metabolism*
  • Phagocytes / microbiology
  • Phagosomes / immunology
  • Phagosomes / metabolism
  • Phagosomes / microbiology
  • Protein Kinase C-alpha / metabolism
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Sepsis / etiology
  • Sepsis / immunology
  • Sepsis / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors / metabolism
  • Ubiquitination
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism
  • rho Guanine Nucleotide Dissociation Inhibitor beta / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Arhgdib protein, mouse
  • ECSIT protein, mouse
  • Minor Histocompatibility Antigens
  • Reactive Oxygen Species
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • rho Guanine Nucleotide Dissociation Inhibitor beta
  • Stk3 protein, mouse
  • Stk4 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Protein Kinase C-alpha
  • rac GTP-Binding Proteins