Abstract
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.
Highlights
Prostate apoptosis response-4 (Par-4) is a protein that was first identified in prostate cancer cells undergoing apoptosis[4,5]
Par-4 expression was analyzed by Western blot using a Par-4 specific antibody. (B) RAW 264.7 cells were infected with at MOI of 1, 5 and 10, and incubated for indicated times. (C) ER stress sensor molecules in H37Ra (MOI = 5)-infected macrophages were detected by Western blot analysis. (D) RAW 264.7 cells were pretreated with 4-PBA (5 μM) for 1 h and infected with H37Ra for 24 h
We show that Par-4 translocation to the plasma membrane is dependent on ER stress-mediated apoptosis in macrophages during Mycobacterium tuberculosis (Mtb) infection
Summary
Prostate apoptosis response-4 (Par-4) is a protein that was first identified in prostate cancer cells undergoing apoptosis[4,5]. Par-4 resides predominantly in the cytosol, but is secreted out of the cell through the plasma membrane in response to apoptotic stress[5]. Secreted Par-4 can induce cancer cell-specific apoptosis[5,6]. Many studies suggest that regulation of apoptosis in mycobacterial-infected cells may be an important mechanism for the removal of intracellular mycobacteria[8,9,10]. Our recent findings demonstrated that ER stress-mediated apoptosis in macrophages is important for reducing intracellular survival of mycobacteria[11]. There is little known about the role of GRP78 during mycobacterial infection[13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
