Identification of substrates of the Mycobacterium tuberculosis proteasome

EMBO J. 2006 Nov 15;25(22):5423-32. doi: 10.1038/sj.emboj.7601405. Epub 2006 Nov 2.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acyl-Carrier Protein S-Malonyltransferase / metabolism*
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Alkaline Phosphatase / genetics
  • Alkaline Phosphatase / metabolism*
  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Hydroxymethyl and Formyl Transferases / metabolism*
  • Mice
  • Mutation
  • Mycobacterium tuberculosis / enzymology*
  • Proteasome Endopeptidase Complex / metabolism*
  • Tuberculosis, Pulmonary / enzymology
  • Tuberculosis, Pulmonary / microbiology


  • Bacterial Proteins
  • Hydroxymethyl and Formyl Transferases
  • 3-methyl-2-oxobutanoate hydroxymethyltransferase
  • Acyl-Carrier Protein S-Malonyltransferase
  • Alkaline Phosphatase
  • periplasmic alkaline phosphatase, Chryseobacterium meningosepticum
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases
  • Mpa protein, Mycobacterium tuberculosis