Identification of a depupylation regulator for an essential enzyme in <i>Mycobacterium tuberculosis</i>
In <i>Mycobacterium tuberculosis (Mtb)</i>, proteins that are posttranslationally modified with a prokaryotic ubiquitin-like protein (Pup) can be degraded by bacterial proteasomes. A single Pup-ligase and depupylase shape the pupylome, but the mechanisms regulating their substrate specificity are incompletely understood. Here, we identified a depupylation regulator, a protein called CoaX, through its copurification with the depupylase Dop. CoaX is a pseudopantothenate kinase that showed evidence of binding to pantothenate, an essential nutrient <i>Mtb</i> synthesizes, but not its phosphorylation. In a ∆<i>coaX</i> mutant, pantothenate synthesis enzymes including PanB, a substrate of the Pup-proteasome system (PPS), were more abundant than in the parental strain. In vitro, CoaX specifically accelerated depupylation of Pup~PanB, while addition of pantothenate inhibited this reaction. In culture, media supplementation with pantothenate decreased PanB levels, which required CoaX. Collectively, we propose CoaX regulates PanB abundance in response to pantothenate levels by modulating its vulnerability to proteolysis by <i>Mtb</i> proteasomes.
Authors
- Nora M. Samhadaneh
- Damian C. Ekiert (ORCID: https://orcid.org/0000-0002-2570-0404)
- L. Aravind (ORCID: https://orcid.org/0000-0003-0771-253X)
- K. Heran Darwin (ORCID: https://orcid.org/0000-0002-5043-7548)
- Shoshanna C. Kahne (ORCID: https://orcid.org/0000-0002-4483-4707)
- Lakshminarayan M. Iyer (ORCID: https://orcid.org/0000-0002-4844-2022)
- Kehilwe C. Nakedi
- Gira Bhabha (ORCID: https://orcid.org/0000-0003-0624-6178)
- Gregory Putzel (ORCID: https://orcid.org/0000-0002-5211-2608)
- Alejandro Pironti (ORCID: https://orcid.org/0000-0002-7759-6776)
- James Chen (ORCID: https://orcid.org/0000-0002-2311-003X)
- Jin Hee Yoo
- Kyu Y. Rhee
Institutions
- Johns Hopkins University (US)
- Cornell University (US)
- National Center for Biotechnology Information (US)
- Weill Cornell Medicine (US)
- New York University (US)
- Core Laboratories (United States) (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1073/pnas.2407239121
- Citations
- 5
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 1.95
Funders
- Bill and Melinda Gates Foundation
- Jane Coffin Childs Memorial Fund for Medical Research
- National Institutes of Health
- Office of Science
- NYU Grossman School of Medicine
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- U.S. National Library of Medicine