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

Research output: Contribution to journalArticle

82 Citations (Scopus)

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
StatePublished - Nov 15 2006

Fingerprint

Proteasome Endopeptidase Complex
Mycobacterium tuberculosis
Substrates
Adenosine Triphosphatases
Accessories
Virulence
Peptide Hydrolases
Acyl Carrier Protein
Polyketides
Degradation
Essential Fatty Acids
Bacterial Proteins
Biosynthesis
Pathogens
Enzymes
Proteolysis
Tyrosine
Nitric Oxide
Proteins
Fatty Acids

Keywords

  • Mpa
  • PafA
  • Proteasome
  • Substrates
  • Tuberculosis

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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

Identification of substrates of the Mycobacterium tuberculosis proteasome. / Pearce, Michael J.; Arora, Pooja; Festa, Richard A.; Butler-Wu, Susan M.; Gokhale, Rajesh S.; Darwin, K. Heran.

In: EMBO Journal, Vol. 25, No. 22, 15.11.2006, p. 5423-5432.

Research output: Contribution to journalArticle

Pearce, MJ, Arora, P, Festa, RA, Butler-Wu, SM, Gokhale, RS & Darwin, KH 2006, 'Identification of substrates of the Mycobacterium tuberculosis proteasome', EMBO Journal, vol. 25, no. 22, pp. 5423-5432. https://doi.org/10.1038/sj.emboj.7601405
Pearce MJ, Arora P, Festa RA, Butler-Wu SM, Gokhale RS, Darwin KH. Identification of substrates of the Mycobacterium tuberculosis proteasome. EMBO Journal. 2006 Nov 15;25(22):5423-5432. https://doi.org/10.1038/sj.emboj.7601405
Pearce, Michael J. ; Arora, Pooja ; Festa, Richard A. ; Butler-Wu, Susan M. ; Gokhale, Rajesh S. ; Darwin, K. Heran. / Identification of substrates of the Mycobacterium tuberculosis proteasome. In: EMBO Journal. 2006 ; Vol. 25, No. 22. pp. 5423-5432.
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