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Published on: February 28, 2025
Mycobacterium tuberculosis Cpn60.2 (GroEL2) blocks macrophage apoptosis via interaction with mitochondrial mortalin
Sunil Joseph1, Alex Yuen1, Vijender Singh1
1Division of Infectious Diseases, Department of Medicine, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
Abstract:
Earlier studies suggested that Mycobacterium tuberculosis (Mtb) proteins exported within the host macrophage play an essential role in tuberculosis pathogenesis. In fact, Mtb proteins interact with and deactivate key regulators of many macrophage functions such as phago-lysosome fusion and antigen presentation, resulting in the intracellular persistence of pathogenic mycobacteria. Cpn60.2 is an abundant Mtb chaperone protein, restricted to cell cytoplasm and surface, that was reported to be essential for bacterial growth. Here, we provide evidence that once Mtb is ingested by the macrophage, Cpn60.2 is able to detach from the bacterial surface and crosses the phagosomal membrane towards mitochondria organelles. Once there, Cpn60.2 interacts with host mortalin, a member of the HSP 70 gene family that contributes to apoptosis modulation. In this regard, we showed that Cpn60.2 blocks macrophage apoptosis, a phenotype that is reversed when cells are pretreated with a specific mortalin inhibitor. Our findings have extended the current knowledge of the Mtb Cpn60.2 functions to add a strong anti-apoptotic activity dependent on its interaction with mitochondrial mortalin, which otherwise promotes Mtb survival in the hostile macrophage environment.
Insights
Mycobacterium tuberculosis (Mtb) protein Cpn60.2 inhibits macrophage apoptosis by interacting with host mortalin. This interaction promotes Mtb survival within macrophages, offering a new therapeutic target for tuberculosis.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Mycobacterium tuberculosis (Mtb) pathogenesis involves proteins exported into host macrophages.
- Mtb proteins disrupt macrophage functions like phagolysosome fusion and antigen presentation, aiding intracellular persistence.
- Cpn60.2, an abundant Mtb chaperone, is crucial for bacterial growth and located on the bacterial surface and cytoplasm.
Purpose of the Study:
- To investigate the function of Mtb Cpn60.2 after macrophage ingestion.
- To determine the interaction of Cpn60.2 with host cell components and its effect on macrophage apoptosis.
Main Methods:
- Tracking Cpn60.2 localization within macrophages post-Mtb ingestion.
- Investigating Cpn60.2 interaction with mitochondrial mortalin.
- Assessing the impact of Cpn60.2 on macrophage apoptosis using mortalin inhibitors.
Main Results:
- Mtb Cpn60.2 detaches from the bacterial surface and enters macrophage mitochondria.
- Cpn60.2 interacts with host mortalin, a protein involved in apoptosis regulation.
- Cpn60.2 inhibits macrophage apoptosis; this effect is reversed by mortalin inhibitors.
Conclusions:
- Mtb Cpn60.2 possesses significant anti-apoptotic activity mediated by its interaction with mitochondrial mortalin.
- This Cpn60.2-mortalin interaction enhances Mtb survival within the macrophage.
- Targeting this interaction could be a novel strategy for tuberculosis treatment.
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