56085 20210121114547.0 doi 10.1074/jbc.M114.631564 sideral 89581 ART-2015-89581 eng Catalán, E. Mouse cytotoxic T cell-derived granzyme B activates the mitochondrial cell death pathway in a bim-dependent fashion 2015 Access copy available to the general public Unrestricted Cytotoxic T cells (Tc) use perforin and granzyme B (gzmB) to kill virus-infected cells and cancer cells. Recent evidence suggests that human gzmB primarily induces apoptosis via the intrinsic mitochondrial pathway by either cleaving Bid or activating Bim leading to the activation of Bak/Bax and subsequent generation of active caspase-3. In contrast, mouse gzmB is thought to predominantly induce apoptosis by directly processing pro-caspase-3. However, in certain mouse cell types gzmB-mediated apoptosis mainly occurs via the mitochondrial pathway. To investigate whether Bim is involved under the latter conditions, we have now employed ex vivo virus-immune mouse Tc that selectively kill by using perforin and gzmB (gzmB+Tc) as effector cells and wild type as well as Bim- or Bak/Bax-deficient spontaneously (3T9) or virus-(SV40) transformed mouse embryonic fibroblast cells as targets. We show that gzmB+Tc-mediated apoptosis (phosphatidylserine translocation, mitochondrial depolarization, cytochrome c release, and caspase-3 activation) was severely reduced in 3T9 cells lacking either Bim or both Bak and Bax. This outcome was related to the ability of Tc cells to induce the degradation of Mcl-1 and Bcl-XL, the anti-apoptotic counterparts of Bim. In contrast, gzmB+Tc-mediated apoptosis was not affected in SV40-transformed mouse embryonic fibroblast cells lacking Bak/Bax. The data provide evidence that Bim participates in mouse gzmB+Tc-mediated apoptosis of certain targets by activating the mitochondrial pathway and suggest that the mode of cell death depends on the target cell. Our results suggest that the various molecular events leading to transformation and/or immortalization of cells have an impact on their relative resistance to the multiple gzmB+Tc-induced death pathways. info:eu-repo/grantAgreement/ES/MINECO/SAF2008-02139 info:eu-repo/grantAgreement/ES/MINECO-FEDER/SAF2011-25390 info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 4.258 2015 BIOCHEMISTRY & MOLECULAR BIOLOGY 71 / 289 = 0.246 2015 Q1 T1 3.126 2015 Biochemistry 2015 Q1 Molecular Biology 2015 Q1 Cell Biology 2015 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion (orcid)0000-0002-8731-4269 Jaime-Sánchez, P. Universidad de Zaragoza (orcid)0000-0001-7897-9173 Aguilo, N. Universidad de Zaragoza Simon, M.M. Froelich, C.J. (orcid)0000-0003-0154-0730 Pardo, J. Universidad de Zaragoza 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 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 290, 11 (2015), 6868-6877 J. biol. chem. Journal of Biological Chemistry 0021-9258 640669 http://zaguan.unizar.es/record/56085/files/texto_completo.pdf Versión publicada 140578 http://zaguan.unizar.es/record/56085/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:56085 articulos driver 2021-01-21-11:20:01 ARTICLE