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

Nature Immunology volume 14, pages 1219–1228 (2013)Cite this article

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Abstract

The mammalian immune system has the ability to discriminate between pathogenic microbes and nonpathogenic microbes to control inflammation. Here we investigated the ubiquitination profiles of host proteins after infection of macrophages with a virulent strain of the intracellular bacterium Legionella pneumophila or a nonpathogenic mutant of L. pneumophila. Only infection with pathogenic L. pneumophila resulted in ubiquitination of positive regulators of the metabolic checkpoint kinase mTOR and led to diminished mTOR activity. Detection of pathogen signatures resulted in translational biasing toward proinflammatory cytokines through mTOR-mediated regulation of cap-dependent translation. Thus, there is a pathogen-detection program in macrophages that stimulates protein ubiquitination and the degradation of regulators of mTOR, which suppresses mTOR function and directs a proinflammatory cytokine program.

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Figure 1: The PI(3)K-AKT-mTOR pathway is suppressed during pathogenic infection with L. pneumophila.
Figure 2: Suppression of mTOR mediates cytokine biasing in response to pathogenic L. pneumophila.
Figure 3: Suppression of mTOR by pathogenic L. pneumophila inhibits cap-dependent translation.
Figure 4: Cytokine biasing results from inhibition of assembly of the eIF4F complex.
Figure 5: Transcript abundance determines sensitivity to inhibition of eIF4F.
Figure 6: Activated Akt is degraded by a pathogen-induced ubiquitination pathway.
Figure 7: The ubiquitination of Akt is important for cytokine biasing.

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Acknowledgements

We thank P. Walters (University of California, San Francisco) for the antibody to puromycin; R. Vance (University of California Berkeley) for the L. pneumophila Δ5less strain; P. Kaiser (University of California Irvine) for the biotinylation sequence expression vector; W. Mothes (Yale University) for the HL116 interferon reporter cell line; A.-M. Dragoi for suggestions and manuscript critique; C. Godecke and F. Sewald for technical assistance with flow cytometry; and X. Liu for assistance with analysis of the proteomics data. Supported by the US National Institutes of Health (AI097847 and AI048770 to C.R.).

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

    Stanimir S Ivanov & Craig R Roy

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  1. Stanimir S Ivanov
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S.S.I. designed and did the experiments, interpreted the data and wrote the manuscript; and C.R.R. designed the experiments, interpreted the data and wrote the manuscript.

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Correspondence to Craig R Roy.

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The authors declare no competing financial interests.

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Ivanov, S., Roy, C. Pathogen signatures activate a ubiquitination pathway that modulates the function of the metabolic checkpoint kinase mTOR. Nat Immunol 14, 1219–1228 (2013). https://doi.org/10.1038/ni.2740

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