Granzyme B-mediated Cytochrome c Release Is Regulated by the Bcl-2 Family Members Bid and Bax

doi:10.1084/jem.192.10.1391

Published online 13 November 2000.

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© The Rockefeller University Press, 0022-1007/2000/11/1391/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 10, November 20, 2000 1391-1402

Original Article

Granzyme B–mediated Cytochrome c Release Is Regulated by the Bcl-2 Family Members Bid and Bax

Jeffrey A. Heibein^a, Ing Swie Goping^a, Michele Barry^b, Michael J. Pinkoski^c, Gordon C. Shore^d, Douglas R. Green^c, and R. Chris Bleackley^a
^a Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
^b Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
^c Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121
^d Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada

Correspondence to: R. Chris Bleackley, Dept. of Biochemistry, 463 Medical Sciences Bldg., University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Tel:780-492-3968 Fax:780-492-0886

Cytotoxic T lymphocytes (CTLs) destroy target cells througha mechanism involving the exocytosis of cytolytic granule componentsincluding granzyme B (grB) and perforin, which have been shownto induce apoptosis through caspase activation. However, grBhas also been linked with caspase-independent disruption ofmitochondrial function. We show here that cytochrome c releaserequires the direct proteolytic cleavage of Bid by grB to generatea 14-kD grB-truncated product (gtBid) that translocates to mitochondria.In turn, gtBid recruits Bax to mitochondria through a caspase-independentmechanism where it becomes integrated into the membrane andinduces cytochrome c release. Our results provide evidence fora new pathway by which CTLs inflict damage and explain the caspase-independentmechanism of mitochondrial dysfunction.

Key Words: cytotoxic T lymphocyte, granzyme B, Bcl-2, Bid, Bax

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Sharma, V., Delgado, M., Ganea, D. (2006). Granzyme B, a New Player in Activation-Induced Cell Death, Is Down-Regulated by Vasoactive Intestinal Peptide in Th2 but Not Th1 Effectors. J. Immunol. 176: 97-110 [Abstract] [Full Text]
Janas, M. L., Groves, P., Kienzle, N., Kelso, A. (2005). IL-2 Regulates Perforin and Granzyme Gene Expression in CD8+ T Cells Independently of Its Effects on Survival and Proliferation. J. Immunol. 175: 8003-8010 [Abstract] [Full Text]
Han, J., Goldstein, L. A., Gastman, B. R., Rabinovitz, A., Rabinowich, H. (2005). Disruption of Mcl-1{middle dot}Bim Complex in Granzyme B-mediated Mitochondrial Apoptosis. J. Biol. Chem. 280: 16383-16392 [Abstract] [Full Text]
Mader, J. S., Salsman, J., Conrad, D. M., Hoskin, D. W. (2005). Bovine lactoferricin selectively induces apoptosis in human leukemia and carcinoma cell lines. Molecular Cancer Therapeutics 4: 612-624 [Abstract] [Full Text]
Waterhouse, N. J., Sedelies, K. A., Browne, K. A., Wowk, M. E., Newbold, A., Sutton, V. R., Clarke, C. J. P, Oliaro, J., Lindemann, R. K., Bird, P. I., Johnstone, R. W., Trapani, J. A. (2005). A Central Role for Bid in Granzyme B-induced Apoptosis. J. Biol. Chem. 280: 4476-4482 [Abstract] [Full Text]
Stewart, T. L., Wasilenko, S. T., Barry, M. (2005). Vaccinia Virus F1L Protein Is a Tail-Anchored Protein That Functions at the Mitochondria To Inhibit Apoptosis. J. Virol. 79: 1084-1098 [Abstract] [Full Text]
Miyazaki, H, Kuwano, K, Yoshida, K, Maeyama, T, Yoshimi, M, Fujita, M, Hagimoto, N, Yoshida, R, Nakanishi, Y (2004). The perforin mediated apoptotic pathway in lung injury and fibrosis. J. Clin. Pathol. 57: 1292-1298 [Abstract] [Full Text]
Pardo, J., Bosque, A., Brehm, R., Wallich, R., Naval, J., Mullbacher, A., Anel, A., Simon, M. M. (2004). Apoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis. J. Cell Biol. 167: 457-468 [Abstract] [Full Text]
Rutigliano, J. A., Graham, B. S. (2004). Prolonged Production of TNF-{alpha} Exacerbates Illness during Respiratory Syncytial Virus Infection. J. Immunol. 173: 3408-3417 [Abstract] [Full Text]
Choy, J. C., Kerjner, A., Wong, B. W., McManus, B. M., Granville, D. J. (2004). Perforin Mediates Endothelial Cell Death and Resultant Transplant Vascular Disease in Cardiac Allografts. Am. J. Pathol. 165: 127-133 [Abstract] [Full Text]
Han, J., Goldstein, L. A., Gastman, B. R., Froelich, C. J., Yin, X.-M., Rabinowich, H. (2004). Degradation of Mcl-1 by Granzyme B: IMPLICATIONS FOR Bim-MEDIATED MITOCHONDRIAL APOPTOTIC EVENTS. J. Biol. Chem. 279: 22020-22029 [Abstract] [Full Text]
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Johnson, H., Scorrano, L., Korsmeyer, S. J., Ley, T. J. (2003). Cell death induced by granzyme C. Blood 101: 3093-3101 [Abstract] [Full Text]
Schmollinger, J. C., Vonderheide, R. H., Hoar, K. M., Maecker, B., Schultze, J. L., Hodi, F. S., Soiffer, R. J., Jung, K., Kuroda, M. J., Letvin, N. L., Greenfield, E. A., Mihm, M., Kutok, J. L., Dranoff, G. (2003). Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction. Proc. Natl. Acad. Sci. USA 100: 3398-3403 [Abstract] [Full Text]
Metkar, S. S., Wang, B., Ebbs, M. L., Kim, J. H., Lee, Y. J., Raja, S. M., Froelich, C. J. (2003). Granzyme B activates procaspase-3 which signals a mitochondrial amplification loop for maximal apoptosis. J. Cell Biol. 160: 875-885 [Abstract] [Full Text]
Sarig, R., Zaltsman, Y., Marcellus, R. C., Flavell, R., Mak, T. W., Gross, A. (2003). BID-D59A Is a Potent Inducer of Apoptosis in Primary Embryonic Fibroblasts. J. Biol. Chem. 278: 10707-10715 [Abstract] [Full Text]
McIlroy, D., Cartron, P.-F., Tuffery, P., Dudoit, Y., Samri, A., Autran, B., Vallette, F. M., Debre, P., Theodorou, I. (2003). A triple-mutated allele of granzyme B incapable of inducing apoptosis. Proc. Natl. Acad. Sci. USA 100: 2562-2567 [Abstract] [Full Text]
Trapani, J. A., Sutton, V. R., Thia, K. Y.T., Li, Y. Q., Froelich, C. J., Jans, D. A., Sandrin, M. S., Browne, K. A. (2003). A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death. J. Cell Biol. 160: 223-233 [Abstract] [Full Text]
Hirst, C. E., Buzza, M. S., Bird, C. H., Warren, H. S., Cameron, P. U., Zhang, M., Ashton-Rickardt, P. G., Bird, P. I. (2003). The Intracellular Granzyme B Inhibitor, Proteinase Inhibitor 9, Is Up-Regulated During Accessory Cell Maturation and Effector Cell Degranulation, and Its Overexpression Enhances CTL Potency. J. Immunol. 170: 805-815 [Abstract] [Full Text]
Zhang, Y., Lehman, J. M., Petti, L. M. (2002). Apoptosis of Mortal Human Fibroblasts Transformed by the Bovine Papillomavirus E5 Oncoprotein. Mol Cancer Res 1: 122-136 [Abstract] [Full Text]
Yin, X.-M., Luo, Y., Cao, G., Bai, L., Pei, W., Kuharsky, D. K., Chen, J. (2002). Bid-mediated Mitochondrial Pathway Is Critical to Ischemic Neuronal Apoptosis and Focal Cerebral Ischemia. J. Biol. Chem. 277: 42074-42081 [Abstract] [Full Text]
Wieckowski, E., Wang, G.-Q., Gastman, B. R., Goldstein, L. A., Rabinowich, H. (2002). Granzyme B-mediated Degradation of T-Cell Receptor {zeta} Chain. Cancer Res. 62: 4884-4889 [Abstract] [Full Text]
Bidere, N., Briet, M., Durrbach, A., Dumont, C., Feldmann, J., Charpentier, B., de Saint-Basile, G., Senik, A. (2002). Selective Inhibition of Dipeptidyl Peptidase I, Not Caspases, Prevents the Partial Processing of Procaspase-3 in CD3-activated Human CD8+ T Lymphocytes. J. Biol. Chem. 277: 32339-32347 [Abstract] [Full Text]
Dukers, D. F., Meijer, C. J. L. M., ten Berge, R. L., Vos, W., Ossenkoppele, G. J., Oudejans, J. J. (2002). High numbers of active caspase 3-positive Reed-Sternberg cells in pretreatment biopsy specimens of patients with Hodgkin disease predict favorable clinical outcome. Blood 100: 36-42 [Abstract] [Full Text]
Igney, F. H., Krammer, P. H. (2002). Immune escape of tumors: apoptosis resistance and tumor counterattack. J. Leukoc. Biol. 71: 907-920 [Abstract] [Full Text]
Thomas, D. A., Scorrano, L., Putcha, G. V., Korsmeyer, S. J., Ley, T. J. (2001). Granzyme B can cause mitochondrial depolarization and cell death in the absence of BID, BAX, and BAK. Proc. Natl. Acad. Sci. USA 98: 14985-14990 [Abstract] [Full Text]
Wasilenko, S. T., Meyers, A. F. A., Vander Helm, K., Barry, M. (2001). Vaccinia Virus Infection Disarms the Mitochondrion-Mediated Pathway of the Apoptotic Cascade by Modulating the Permeability Transition Pore. J. Virol. 75: 11437-11448 [Abstract] [Full Text]
Hirst, C. E., Buzza, M. S., Sutton, V. R., Trapani, J. A., Loveland, K. L., Bird, P. I. (2001). Perforin-independent expression of granzyme B and proteinase inhibitor 9 in human testis and placenta suggests a role for granzyme B-mediated proteolysis in reproduction. Mol Hum Reprod 7: 1133-1142 [Abstract] [Full Text]
Wang, X. (2001). The expanding role of mitochondria in apoptosis. Genes Dev. 15: 2922-2933 [Full Text]
Wang, G.-Q., Wieckowski, E., Goldstein, L. A., Gastman, B. R., Rabinovitz, A., Gambotto, A., Li, S., Fang, B., Yin, X.-M., Rabinowich, H. (2001). Resistance to Granzyme B-mediated Cytochrome c Release in Bak-deficient Cells. J. Exp. Med. 194: 1325-1338 [Abstract] [Full Text]
Jerome, K. R., Chen, Z., Lang, R., Torres, M. R., Hofmeister, J., Smith, S., Fox, R., Froelich, C. J., Corey, L. (2001). HSV and Glycoprotein J Inhibit Caspase Activation and Apoptosis Induced by Granzyme B or Fas. J. Immunol. 167: 3928-3935 [Abstract] [Full Text]
Wang, J., Guan, E., Roderiquez, G., Norcross, M. A. (2001). Synergistic Induction of Apoptosis in Primary CD4+ T Cells by Macrophage-Tropic HIV-1 and TGF-{beta}1. J. Immunol. 167: 3360-3366 [Abstract] [Full Text]
Medema, J. P., de Jong, J., Peltenburg, L. T. C., Verdegaal, E. M. E., Gorter, A., Bres, S. A., Franken, K. L. M. C., Hahne, M., Albar, J. P., Melief, C. J. M., Offringa, R. (2001). Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc. Natl. Acad. Sci. USA 10.1073/pnas.201398198v1 [Abstract] [Full Text]
Medema, J. P., Schuurhuis, D. H., Rea, D., van Tongeren, J., de Jong, J., Bres, S. A., Laban, S., Toes, R. E.M., Toebes, M., Schumacher, T. N.M., Bladergroen, B. A., Ossendorp, F., Kummer, J. A., Melief, C. J.M., Offringa, R. (2001). Expression of the Serpin Serine Protease Inhibitor 6 Protects Dendritic Cells from Cytotoxic T Lymphocyte-induced Apoptosis: Differential Modulation by T Helper Type 1 and Type 2 Cells. J. Exp. Med. 194: 657-668 [Abstract] [Full Text]
Hallermalm, K., Seki, K., Wei, C., Castelli, C., Rivoltini, L., Kiessling, R., Levitskaya, J. (2001). Tumor necrosis factor-{alpha} induces coordinated changes in major histocompatibility class I presentation pathway, resulting in increased stability of class I complexes at the cell surface. Blood 98: 1108-1115 [Abstract] [Full Text]
Kaspar, A. A., Okada, S., Kumar, J., Poulain, F. R., Drouvalakis, K. A., Kelekar, A., Hanson, D. A., Kluck, R. M., Hitoshi, Y., Johnson, D. E., Froelich, C. J., Thompson, C. B., Newmeyer, D. D., Anel, A., Clayberger, C., Krensky, A. M. (2001). A Distinct Pathway of Cell-Mediated Apoptosis Initiated by Granulysin. J. Immunol. 167: 350-356 [Abstract] [Full Text]
Cuddeback, S. M., Yamaguchi, H., Komatsu, K., Miyashita, T., Yamada, M., Wu, C., Singh, S., Wang, H.-G. (2001). Molecular Cloning and Characterization of Bif-1. A NOVEL Src HOMOLOGY 3 DOMAIN-CONTAINING PROTEIN THAT ASSOCIATES WITH Bax. J. Biol. Chem. 276: 20559-20565 [Abstract] [Full Text]
Denecker, G., Declercq, W., Geuijen, C. A. W., Boland, A., Benabdillah, R., van Gurp, M., Sory, M.-P., Vandenabeele, P., Cornelis, G. R. (2001). Yersinia enterocolitica YopP-induced Apoptosis of Macrophages Involves the Apoptotic Signaling Cascade Upstream of Bid. J. Biol. Chem. 276: 19706-19714 [Abstract] [Full Text]
Zhao, Y., Li, S., Childs, E. E., Kuharsky, D. K., Yin, X.-M. (2001). Activation of Pro-death Bcl-2 Family Proteins and Mitochondria Apoptosis Pathway in Tumor Necrosis Factor-alpha -induced Liver Injury. J. Biol. Chem. 276: 27432-27440 [Abstract] [Full Text]
Wang, G.-Q., Gastman, B. R., Wieckowski, E., Goldstein, L. A., Gambotto, A., Kim, T.-H., Fang, B., Rabinovitz, A., Yin, X.-M., Rabinowich, H. (2001). A Role for Mitochondrial Bak in Apoptotic Response to Anticancer Drugs. J. Biol. Chem. 276: 34307-34317 [Abstract] [Full Text]
Basanez, G., Zhang, J., Chau, B. N., Maksaev, G. I., Frolov, V. A., Brandt, T. A., Burch, J., Hardwick, J. M., Zimmerberg, J. (2001). Pro-apoptotic Cleavage Products of Bcl-xL Form Cytochrome c-conducting Pores in Pure Lipid Membranes. J. Biol. Chem. 276: 31083-31091 [Abstract] [Full Text]
Medema, J. P., de Jong, J., Peltenburg, L. T. C., Verdegaal, E. M. E., Gorter, A., Bres, S. A., Franken, K. L. M. C., Hahne, M., Albar, J. P., Melief, C. J. M., Offringa, R. (2001). Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc. Natl. Acad. Sci. USA 98: 11515-11520 [Abstract] [Full Text]