165904 20260116002211.0 doi 10.1038/cddis.2014.313 sideral 87605 ART-2014-87605 eng Aguiló, N. Universidad de Zaragoza (orcid)0000-0001-7897-9173 Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis 2014 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. Access copy available to the general public Unrestricted info:eu-repo/semantics/openAccess All rights reserved http://www.europeana.eu/rights/rr-f/ 5.014 2014 CELL BIOLOGY 49 / 184 = 0.266 2014 Q2 T1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Uranga, S. Universidad de Zaragoza (orcid)0000-0001-7866-2803 Marinova, D. Universidad de Zaragoza (orcid)0000-0001-8644-120X Martín, C. Universidad de Zaragoza (orcid)0000-0003-2993-5478 Pardo, J. Universidad de Zaragoza (orcid)0000-0003-0154-0730 1008 630 Universidad de Zaragoza Dpto. Microb.Med.Pr.,Sal.Públ. Área Microbiología 1008 566 Universidad de Zaragoza Dpto. Microb.Med.Pr.,Sal.Públ. Área Inmunología 1008 X Universidad de Zaragoza Dpto. Microb.Med.Pr.,Sal.Públ. Proy. investigación HQA 5, 7 (2014), e1343 [10 pp.] Cell death dis. CELL DEATH & DISEASE 2041-4889 2128062 http://zaguan.unizar.es/record/165904/files/texto_completo.pdf Versión publicada 3542098 http://zaguan.unizar.es/record/165904/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:165904 articulos driver 2026-01-15-21:56:15 ARTICLE