The Role of Prostate Apoptosis Response-4 (Par-4) in Mycobacterium tuberculosis Infected Macrophages

Area of Science:

• Cellular Biology
• Immunology
• Cancer Research

Background:

• Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein.
• Endoplasmic reticulum (ER) stress-induced apoptosis is crucial for host defense against Mycobacterium tuberculosis (Mtb).
• The role of Par-4 in ER stress and Mtb infection was previously unexplored.

Purpose of the Study:

• To investigate the function of Par-4 in ER stress-induced apoptosis during mycobacterial infection.
• To elucidate the mechanism by which Par-4 influences Mtb survival in host cells.
• To examine the impact of Bacillus Calmette-Guérin (BCG) on Par-4 and caspase activation in prostate cancer cells.

Main Methods:

• Quantified Par-4 and GRP78 protein levels in Mtb-infected macrophages.
• Assessed translocation of Par-4 and GRP78 to the macrophage surface.
• Analyzed caspase activation, NF-κB activation, and ER stress markers.
• Manipulated Par-4 expression (overexpression and knockdown) to study Mtb intracellular survival.
• Examined Par-4, GRP78, and caspase activation in BCG-infected prostate cancer cells.

Main Results:

• Par-4 and GRP78 protein levels increased upon Mtb infection and translocated to the surface of infected macrophages.
• Par-4 and GRP78 induced apoptosis via caspase activation in Mtb-infected macrophages.
• Reactive oxygen species (ROS) inhibition reduced NF-κB activation, ER stress, and Par-4 production.
• Par-4 overexpression reduced Mtb H37Ra growth, while knockdown increased it.
• BCG infection elevated Par-4, GRP78, and caspase activation in prostate cancer cells.

Conclusions:

• ER stress-induced Par-4 functions as a host defense mechanism against mycobacterial infection.
• Par-4 contributes to reduced intracellular mycobacterial survival.
• BCG treatment enhances Par-4-dependent caspase activation in prostate cancer cells, suggesting a role in cancer regulation.