Comparative analysis of macrophage post-translational modifications during intracellular bacterial pathogen infection

Johnson, J. R.; Parry, T.; Repasy, T.; Geiger, K. M.; Verschueren, E.; Budzik, J. M.; Jimenez-Morales, D.; Newton, B. W.; Powell, E.; Coscoy, L.; Portnoy, D. A.; Krogan, N. J.; Cox, J. S.

doi:10.1101/2020.05.27.116772

bioRxiv · 10.1101/2020.05.27.116772

Comparative analysis of macrophage post-translational modifications during intracellular bacterial pathogen infection

Johnson, J. R.·Parry, T.·Repasy, T.·Geiger, K. M.·Verschueren, E.·Budzik, J. M.·Jimenez-Morales, D.·Newton, B. W.·Powell, E.·Coscoy, L.·Portnoy, D. A.·Krogan, N. J.·Cox, J. S.

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Abstract

Macrophages activate robust antimicrobial functions upon engulfing virulent bacteria, yet a wide array of pathogens paradoxically thrive within these innate immune cells. To probe the pathogen-macrophage interface, we used proteomics to comprehensively quantify changes in post-translational modifications (PTMs) of host proteins during infection with three evolutionarily diverse intracellular pathogens: Mycobacterium tuberculosis, Salmonella enterica serovar Typhimurium, and Listeria monocytogenes. Comparing global phosphorylation and ubiquitylation patterns identified extensive reprogramming of cellular pathways during infection, with ubiquitylation patterns revealing unique pathogen-specific molecular response signatures undetectable by transcriptional profiling. Differential PTM changes during infection with attenuated M. tuberculosis cells lacking the ESX-1 virulence determinant revealed extensive modification of phagosome dynamics and antiviral type I interferon activation. We found that M. tuberculosis-mediated activation of the antiviral OASL1-IRF7 pathway promotes bacterial replication, uncovering a new mechanism of virus-bacterial synergy. Our data reveals remarkable specificity in innate cellular responses to complex stimuli and provides a resource for deeper understanding of host-pathogen interactions.

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Johnson, J. R., Parry, T., Repasy, T., Geiger, K. M., Verschueren, E., Budzik, J. M., Jimenez-Morales, D., Newton, B. W., Powell, E., Coscoy, L., Portnoy, D. A., Krogan, N. J., Cox, J. S.. 2020-05-27. Comparative analysis of macrophage post-translational modifications during intracellular bacterial pathogen infection. https://doi.org/10.1101/2020.05.27.116772

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