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Pathogen signatures activate a ubiquitination pathway that modulates the function of the metabolic checkpoint kinase

Stanimir S Ivanov1, Craig R Roy

  • 1Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA.

Nature Immunology
|October 15, 2013
PubMed

Insights

Pathogenic bacteria trigger protein ubiquitination in macrophages, suppressing the mTOR pathway. This leads to increased production of pro-inflammatory cytokines, a key immune response.

Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • The mammalian immune system distinguishes between pathogenic and nonpathogenic microbes to regulate inflammation.
  • Macrophages play a critical role in detecting and responding to microbial infections.

Purpose of the Study:

  • To investigate the ubiquitination profiles of host proteins in macrophages following infection with pathogenic versus nonpathogenic Legionella pneumophila.
  • To elucidate the role of the mechanistic target of rapamycin (mTOR) pathway in the macrophage response to bacterial infection.

Main Methods:

  • Macrophage infection with virulent and nonpathogenic strains of Legionella pneumophila.
  • Analysis of host protein ubiquitination patterns.
  • Assessment of mTOR activity and its downstream effects on protein translation.

Main Results:

  • Infection with pathogenic Legionella pneumophila, but not the nonpathogenic mutant, induced ubiquitination of positive mTOR regulators.
  • Pathogen detection led to diminished mTOR activity.
  • mTOR-mediated regulation of cap-dependent translation was biased towards pro-inflammatory cytokine production.

Conclusions:

  • Macrophages possess a pathogen-detection program that initiates protein ubiquitination and degradation of mTOR regulators.
  • Suppression of mTOR function by this program directs a pro-inflammatory cytokine response.
  • This mechanism highlights a critical interplay between microbial virulence, host protein modification, and immune signaling.

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