Tuberculosis kills about 2 million people globally every year. A key defense against Mycobacterium tuberculosis (Mtb) infections is the production of nitric oxide (NO) by macrophages. Although NO controls Mtb growth, it rarely sterilizes the bacterium from the host, suggesting Mtb has mechanisms to resist NO toxicity. The Mtb proteasome is one such mechanism that is required for resistance to NO as well as causing death in mice. Thus, we are interested in targeting the proteasome and its associated factors for drug development. The proteasome is a multi-subunit, barrel shaped complex that degrades proteins. We found that the proteins Mpa and PafA are required for protein degradation: Mpa is thought to chaperone proteins into the proteasome core and PafA appears to be required for the attachment of a prokaryotic ubiquitin-like protein (Pup) onto substrates targeted for destruction. Pup represents the first known post-translational small protein modifier identified in any prokaryote. Little is known about how Pup is conjugated to its target substrates thus we propose to identify and characterize all proteins required for pupylation using genetic, biochemical and molecular biological techniques. In addition, we have recently discovered pupylation is reversible, thus we are in the process of characterizing the depupylation pathway. The elucidation of the Pup-proteasome sytem of Mtb will hopefully lay the foundation for the discovery and characterization of other posttranslational modification systems in all bacteria. Furthermore, these enzymes may represent new targets for the development of anti- tuberculosis drugs.
Tuberculosis therapy takes 6-9 months, a problem that leads to decreased compliance for taking antibiotics and increased chances of developing drug-resistance. The rise of extensively drug resistant (XDR) strains of M. tuberculosis has become a great public concern as it has recently made headlines in the popular press. Thus the new treatments for tuberculosis are needed now, and the pupylation pathway may provide new targets for drug development.
|Hu, Kuan; Jastrab, Jordan B; Zhang, Susan et al. (2018) Proteasome substrate capture and gate opening by the accessory factor PafE from Mycobacterium tuberculosis. J Biol Chem 293:4713-4723|
|Jastrab, Jordan B; Samanovic, Marie I; Copin, Richard et al. (2017) Loss-of-Function Mutations in HspR Rescue the Growth Defect of a Mycobacterium tuberculosis Proteasome Accessory Factor E (pafE) Mutant. J Bacteriol 199:|
|Zhang, Susan; Burns-Huang, Kristin E; Janssen, Guido V et al. (2017) Mycobacterium tuberculosis Proteasome Accessory Factor A (PafA) Can Transfer Prokaryotic Ubiquitin-Like Protein (Pup) between Substrates. MBio 8:|
|Wu, Yujie; Hu, Kuan; Li, Defeng et al. (2017) Mycobacterium tuberculosis proteasomal ATPase Mpa has a ?-grasp domain that hinders docking with the proteasome core protease. Mol Microbiol 105:227-241|
|Bai, Lin; Jastrab, Jordan B; Isasa, Marta et al. (2017) Structural Analysis of Mycobacterium tuberculosis Homologues of the Eukaryotic Proteasome Assembly Chaperone 2 (PAC2). J Bacteriol 199:|
|Becker, Samuel H; Darwin, K Heran (2017) Bacterial Proteasomes: Mechanistic and Functional Insights. Microbiol Mol Biol Rev 81:|
|Samanovic, Marie I; Darwin, K Heran (2016) Game of 'Somes: Protein Destruction for Mycobacterium tuberculosis Pathogenesis. Trends Microbiol 24:26-34|
|Bai, Lin; Hu, Kuan; Wang, Tong et al. (2016) Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 113:E1983-92|
|Jastrab, Jordan B; Wang, Tong; Murphy, J Patrick et al. (2015) An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 112:E1763-72|
|Jastrab, Jordan B; Darwin, K Heran (2015) Bacterial Proteasomes. Annu Rev Microbiol 69:109-27|
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