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  • The EMBO Journal (2006) 25, 5423 - 5432
  • doi:10.1038/sj.emboj.7601405

Published online: 2 November 2006

Identification of substrates of the Mycobacterium tuberculosis proteasome

Michael J Pearce1, Pooja Arora2,a, Richard A Festa1, Susan M Butler-Wu1, Rajesh S Gokhale2 and K Heran Darwin1

  1. Department of Microbiology, New York University School of Medicine, New York, NY, USA
  2. National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India

Correspondence to:

K Heran Darwin, Department of Microbiology, New York University School of Medicine, 550 First Avenue, Medical Sciences Building Room 236, New York, NY 10016, USA. Tel.: +1 212 263 2624; Fax: +1 212 263 8276; E-mail: heran.darwin@med.nyu.edu

aPresent address: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA

Received 24 July 2006; Accepted 5 October 2006

The putative proteasome-associated proteins Mpa (Mycobateriumproteasomal 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.

  • Keywords:

    • Mpa,
    • PafA,
    • proteasome,
    • substrates,
    • tuberculosis