RESUMEN
Cytotoxic lymphocytes protect their host from viral infection and cellular transformation by delivering a range of toxins stored within intracellular granules. One of the most potent of these toxins is the serine protease granzyme B. This review will discuss mechanisms used by granzyme B to enter target cells and the ways in which it synergizes with other granule toxins to cause cell death.
Asunto(s)
Apoptosis , Serina Endopeptidasas/metabolismo , Linfocitos T Citotóxicos/enzimología , Animales , Proteína Proapoptótica que Interacciona Mediante Dominios BH3 , Proteínas Portadoras/metabolismo , Caspasa 3 , Caspasas/metabolismo , Granzimas , Humanos , Mitocondrias/patología , Serina Endopeptidasas/química , Serina Endopeptidasas/genética , Serina Endopeptidasas/inmunología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Granzyme B, a protease released from cytotoxic lymphocytes, has been proposed to induce target cell death by cleaving and activating the pro-apoptotic Bcl-2 family member Bid. It has also been proposed that granzyme B can induce target cell death by activating caspases directly, by cleaving caspase substrates, and/or by cleaving several non-caspase substrates. The relative importance of Bid in granzyme B-induced cell death has therefore remained unclear. Here we report that cells isolated from various tissues of Bid-deficient mice were resistant to granzyme B-induced cell death. Consistent with the proposed role of Bid in regulating mitochondrial outer membrane permeabilization, cytochrome c remained in the mitochondria of Bid-deficient cells treated with granzyme B. Unlike wild type cells, Bid-deficient cells survived and were then able to proliferate normally, demonstrating the critical role for Bid in mediating granzyme B-induced apoptosis.
Asunto(s)
Apoptosis , Proteínas Portadoras/fisiología , Serina Endopeptidasas/metabolismo , Animales , Proteína Proapoptótica que Interacciona Mediante Dominios BH3 , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Muerte Celular , Proliferación Celular , Células Cultivadas , Cromo/metabolismo , Citocromos c/metabolismo , Dendritas/metabolismo , Células Dendríticas , Relación Dosis-Respuesta a Droga , Fibroblastos/metabolismo , Granzimas , Membranas Intracelulares/metabolismo , Linfocitos/metabolismo , Linfoma de Células B/metabolismo , Potenciales de la Membrana , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Factores de TiempoRESUMEN
Apoptosis in response to granzyme B involves activation of caspase-dependent target cell death pathways. Herein, we show that granzyme B initiates caspase processing but cannot fully process procaspase-3 in intact Jurkat T leukemia or NT2 neuronal cells. Rather, the release from mitochondria of proapoptotic mediators cytochrome c, Smac/Diablo, and HtrA2/Omi facilitates full activation of caspases that results from autoprocessing. Bcl-2 overexpression in mitochondria suppresses the release of these proapoptotic molecules, resulting in cell survival despite partial procaspase processing by granzyme B. We propose that binding of inhibitor of apoptosis (IAP) proteins to partially processed procaspases inhibits cell death unless mitochondrial disruption also occurs in response to granzyme B or activated BH3-domain proteins such as truncated Bid.