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Identifying functional ubiquitylation during intracellular bacterial pathogen infection

  • Author(s): Parry, Trevor J.
  • Advisor(s): Cox, Jeffery S
  • et al.
Abstract

Ubiquitin and ubiquitin-like proteins impart regulatory information during innate immune responses to infection, but the scope of their role in coordinating the responses of immune cells to infection is unknown. Recent advances in immmunoaffinity purification of ubiquitylated peptides, paired with high accuracy mass-spectrometry, have provided a new platform to measure global cellular ubiquitylation with extraordinary depth. Here we report the application of this methodology to quantitatively measure changes in ubiquitylation of the macrophage proteome during infection with three intracellular bacterial pathogens: Mycobacterium tuberculosis, Salmonella enterica serovar Typhimurium, and Listeria monocytogenes. This has revealed thousands of ubiquitylation events that occur early after infection, most of which were previously unknown. Unlike transcriptional responses to bacterial infection, which are largely monotonic, our results reveal a surprising diversity in ubiquitin-mediated responses to each pathogen. Likewise, using well-defined attenuated bacterial mutants revealed a remarkable ability of macrophages to discriminate virulent from non-virulent bacteria, suggesting macrophages can integrate information about the nature of the engulfed bacteria and elicit unique responses. Many of these changes likely play functional roles in host resistance, as we have identified a novel ubiquitin-modified pathway, the antiviral OASL1-IRF7 pathway, that is critical for Mycobacterium tuberculosis growth in vitro and in vivo.

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