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Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells
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Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells
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Journal Article
Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells
2011
Overview
Natural killer cells and cytotoxic T lymphocytes kill targeted cells by releasing granzymes and perforin. Lieberman and colleagues show that these lethal molecules first accumulate in endocytic vesicles, where perforin generates pores that leak granzymes into the cytosol.
How the pore-forming protein perforin delivers apoptosis-inducing granzymes to the cytosol of target cells is uncertain. Perforin induces a transient Ca
2+
flux in the target cell, which triggers a process to repair the damaged cell membrane. As a consequence, both perforin and granzymes are endocytosed into enlarged endosomes called 'gigantosomes'. Here we show that perforin formed pores in the gigantosome membrane, allowing endosomal cargo, including granzymes, to be gradually released. After about 15 min, gigantosomes ruptured, releasing their remaining content. Thus, perforin delivers granzymes by a two-step process that involves first transient pores in the cell membrane that trigger the endocytosis of granzyme and perforin and then pore formation in endosomes to trigger cytosolic release.
Publisher
Nature Publishing Group US,Nature Publishing Group
