Tuberculosis (TB) kills about 1.5 million people globally every year, making it the leading cause of death by a bacterial pathogen. The lack of an effective TB vaccine or the development of protective immunity after TB infection suggests antimicrobial drugs may be our best chance for controlling this disease. Current therapies are prolonged and toxic, and drug resistance is on the rise. Thus the TB field is eager to identify new drugs that are less toxic as well as more efficacious against drug-resistant strains. The Mycobacterium tuberculosis (Mtb) proteasome is essential for this bacterium to cause lethal infections in animals; thus, we want to understand how proteasome function is linked to Mtb physiology as well as target the proteasome and its co-factors for drug development. The proteasome is a multi-subunit, barrel shaped complex that degrades proteins. We found that enzymes required for protein degradation include PafA, which attaches prokaryotic ubiquitin-like protein (Pup) onto substrates targeted for destruction, and Mpa, which is an ATPase chaperone that recognizes pupylated proteins and unfolds them for delivery into the Mtb proteasome core. Pup can also be removed from substrates by a highly unique protease called Dop. More recently, we discovered a new co-factor called PafE, which forms dodecameric rings that open the proteasome to degrade proteins in an ATP-independent manner. Interestingly, PafE does not require Pup or any other post-translational modification to recognize proteins for degradation. This proposal outlines experiments that will determine how proteins are selected for Pup/Mpa-dependent and PafE-dependent proteasomal degradation, and determine the roles of PafE-dependent substrates on Mtb physiology and pathogenesis.

Public Health Relevance

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 strains of M. tuberculosis is a tremendous public concern as it has recently made headlines in the popular press. Thus, new treatments for tuberculosis are needed now, and the M. tuberculosis proteasome and the pathways it regulates may provide new targets for tuberculosis therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI088075-09
Application #
9741036
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Mendez, Susana
Project Start
2010-04-01
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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:
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
Samanovic, Marie I; Darwin, K Heran (2016) Game of 'Somes: Protein Destruction for Mycobacterium tuberculosis Pathogenesis. Trends Microbiol 24:26-34
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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