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Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that forms a complex with glucose-regulated protein 78 (GRP78) to induce apoptosis. Previously, we reported that ER stress-induced apoptosis is a critical host defense mechanism against  Mycobacterium tuberculosis (Mtb ). We sought to understand the role of Par-4 during ER stress-induced apoptosis in response to mycobacterial infection. Par-4 and GRP78 protein levels increased in response  Mtb  (strain: H37Ra) infection. Furthermore, Par-4 and GRP78 translocate to the surface of  Mtb  H37Ra-infected macrophages and induce apoptosis via caspase activation. NF-κB activation , Mtb -mediated ER stress, and Par-4 production were significantly diminished in macrophages with inhibited ROS production. To test Par-4 function during mycobacterial infection, we analyzed intracellular survival of  Mtb  H37Ra in macrophages with Par-4 overexpression or knockdown.  Mtb  H37Ra growth was significantly reduced in Par-4 overexpressing macrophages and increased in knockdown macrophages. We also observed increased Par-4, GRP78, and caspases activation in Bacillus Calmette-Guérin (BCG)-infected prostate cancer cells. Our data demonstrate that Par-4 is associated with ER stress-induced apoptosis resulting in reduced intracellular survival of mycobacteria. BCG treatment increases Par-4-dependent caspase activation in prostate cancer cells. These results suggest ER stress-induced Par-4 acts as an important defense mechanism against mycobacterial infection and regulates cancer.

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