title: Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis.
abstract: Mycobacterium tuberculosis, the causative agent of tuberculosis, induces apoptosis in infected macrophages in vitro and in vivo. However, the molecular mechanism controlling this process is not known. In order to study the involvement of the mitochondrial apoptotic pathway in M. tuberculosis-induced apoptosis, we analysed cell death in M. tuberculosis-infected embryonic fibroblasts (MEFs) derived from different knockout mice for genes involved in this route. We found that apoptosis induced by M. tuberculosis is abrogated in the absence of Bak and Bax, caspase 9 or the executioner caspases 3 and 7. Notably, we show that MEF deficient in the BH3-only BCL-2-interacting mediator of cell death (Bim) protein were also resistant to this process. The relevance of these results has been confirmed in the mouse macrophage cell line J774, where cell transfection with siRNA targeting Bim impaired apoptosis induced by virulent mycobacteria. Notably, only infection with a virulent strain, but not with attenuated ESX-1-defective strains, such as Bacillus Calmette-Guerin and live-attenuated M. tuberculosis vaccine strain MTBVAC, induced Bim upregulation and apoptosis, probably implicating virulence factor early secreted antigenic target 6-kDa protein in this process. Our results suggest that Bim upregulation and apoptosis is mediated by the p38MAPK-dependent pathway. Our findings show that Bim is a master regulator of apoptosis induced by M. tuberculosis.
authors.affiliation: 1] Grupo de Genética de Micobacterias. Dpto. Microbiología, Medicina Preventiva y Salud Pública, Facultad de Medicina, Universidad de Zaragoza, C/ Domingo Miral s/n, 50009 Zaragoza, Spain [2] CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Aguiló
authors.affiliation: 1] Grupo de Genética de Micobacterias. Dpto. Microbiología, Medicina Preventiva y Salud Pública, Facultad de Medicina, Universidad de Zaragoza, C/ Domingo Miral s/n, 50009 Zaragoza, Spain [2] CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Uranga
authors.affiliation: 1] Grupo de Genética de Micobacterias. Dpto. Microbiología, Medicina Preventiva y Salud Pública, Facultad de Medicina, Universidad de Zaragoza, C/ Domingo Miral s/n, 50009 Zaragoza, Spain [2] CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Marinova
authors.affiliation: 1] Grupo de Genética de Micobacterias. Dpto. Microbiología, Medicina Preventiva y Salud Pública, Facultad de Medicina, Universidad de Zaragoza, C/ Domingo Miral s/n, 50009 Zaragoza, Spain [2] CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain [3] Servicio de Microbiología, Hospital Universitario Miguel Servet, ISS Aragón, Paseo Isabel la Católica 1-3, 50009 Zaragoza, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Martín
authors.affiliation: 1] Grupo Apoptosis, Inmunidad y Cáncer, Dpto. Bioquímica y Biología Molecular y Celular, Fac. Ciencias, Universidad de Zaragoza, Zaragoza, Spain [2] Cell Immunity in Inflammation, Infection and Cancer Group, Department Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza, Spain [3] Immune Effector Cells Group (ICE), Aragón Health Research Institute (IIS Aragón), Edificio CIBA, Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain [4] Nanoscience Institute of Aragon (INA), University of Zaragoza, Zaragoza, Spain [5] Fundación Aragón I+D (ARAID), Gobierno de Aragón, Zaragoza, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Pardo
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014376:Tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein; D053148:Caspase 3