title: The Role of Prostate Apoptosis Response-4 (Par-4) in Mycobacterium tuberculosis Infected Macrophages.
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.
authors.affiliation: Department of Medical Science, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.|Department of Microbiology, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea.
authors.forename: Ji-Ye
authors.initials: JY
authors.lastname: Han
authors.affiliation: Department of Medical Science, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.|Department of Microbiology, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea.
authors.forename: Yun-Ji
authors.initials: YJ
authors.lastname: Lim
authors.affiliation: Department of Medical Science, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.|Department of Microbiology, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea.
authors.forename: Ji-Ae
authors.initials: JA
authors.lastname: Choi
authors.affiliation: Department of Medical Science, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.|Department of Microbiology, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Medical Science, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.|Department of Microbiology, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Jo
authors.affiliation: Department of Medical Science, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.|Department of Microbiology, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea.
authors.forename: Sung-Man
authors.initials: SM
authors.lastname: Oh
authors.affiliation: Department of Medical Science, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.|Department of Microbiology, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea.|Research Institute for Medical Sciences, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea.
authors.forename: Chang-Hwa
authors.initials: CH
authors.lastname: Song
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D008297:Male; D051379:Mice; D009164:Mycobacterium Infections / Q000378:metabolism* / Q000473:pathology; D009163:Mycobacterium bovis; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000382:microbiology; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C101296:prostate apoptosis response-4 protein