Identification of substrates of the Mycobacterium tuberculosis proteasome

Michael J. Pearce, Pooja Arora, Richard A. Festa, Susan M. Butler-Wu, Rajesh S. Gokhale, K. Heran Darwin

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Abstract

The putative proteasome-associated proteins Mpa (Mycobaterium proteasomal ATPase) and PafA (proteasome accessory factor A) of the human pathogen Mycobacterium tuberculosis (Mtb) are essential for virulence and resistance to nitric oxide. However, a direct link between the proteasome protease and Mpa or PafA has never been demonstrated. Furthermore, protein degradation by bacterial proteasomes in vitro has not been accomplished, possibly due to the failure to find natural degradation substrates or other necessary proteasome co-factors. In this work, we identify the first bacterial proteasome substrates, malonyl Co-A acyl carrier protein transacylase and ketopantoate hydroxymethyltransferase, enzymes that are required for the biosynthesis of fatty acids and polyketides that are essential for the pathogenesis of Mtb. Maintenance of the physiological levels of these enzymes required Mpa and PafA in addition to proteasome protease activity. Mpa levels were also regulated in a proteasome-dependent manner. Finally, we found that a conserved tyrosine of Mpa was essential for function. Thus, these results suggest that Mpa, PafA, and the Mtb proteasome degrade bacterial proteins that are important for virulence in mice.

Original languageEnglish (US)
Pages (from-to)5423-5432
Number of pages10
JournalEMBO Journal
Volume25
Issue number22
DOIs
Publication statusPublished - Nov 15 2006

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Keywords

  • Mpa
  • PafA
  • Proteasome
  • Substrates
  • Tuberculosis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Pearce, M. J., Arora, P., Festa, R. A., Butler-Wu, S. M., Gokhale, R. S., & Darwin, K. H. (2006). Identification of substrates of the Mycobacterium tuberculosis proteasome. EMBO Journal, 25(22), 5423-5432. https://doi.org/10.1038/sj.emboj.7601405