Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells.
Jerome Thiery,Dennis Keefe,Dennis Keefe,Steeve Boulant,Steeve Boulant,Emmanuel Boucrot,Emmanuel Boucrot,Michael Walch,Michael Walch,Denis Martinvalet,Denis Martinvalet,Denis Martinvalet,Ing Swie Goping,R. Chris Bleackley,Tomas Kirchhausen,Tomas Kirchhausen,Judy Lieberman,Judy Lieberman +17 more
TLDR
It is shown that perforin formed pores in the gigantosome membrane, allowing endosomal cargo, including granzymes, to be gradually released.Abstract:
How the pore-forming protein perforin delivers apoptosis-inducing granzymes to the cytosol of target cells is uncertain. Perforin induces a transient Ca2+ 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.read more
Citations
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Natural killer cells enhance the immune surveillance of cancer
TL;DR: In this article, the impact of natural killer cells in cancer control and how NK efficiency can be further enhanced is discussed. But, the authors only focused on the effect of the complementary domain (CD86) on dendritic cells (DCs).
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A high yield and cost-efficient expression system of human granzymes in mammalian cells
Farokh Dotiwala,Isabelle Fellay,Luis Filgueira,Denis Martinvalet,Judy Lieberman,Michael Walch +5 more
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Targeting of Perforin Inhibitor into the Brain Parenchyma Via a Prodrug Approach Can Decrease Oxidative Stress and Neuroinflammation and Improve Cell Survival
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Targeted Cell-to-Cell Delivery of Protein Payloads via the Granzyme-Perforin Pathway.
Daniel J Woodsworth,Lisa Dreolini,Libin Abraham,Robert A. Holt,Robert A. Holt,Robert A. Holt +5 more
TL;DR: The results illustrate that by using granzyme B as a molecular chaperone the granzyme-perforin pathway can be exploited as a programmable molecular delivery system for cell-based therapies.
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Noncytotoxic functions of killer cell granzymes in viral infections
TL;DR: In this article, the authors summarize current evidence for the noncytotoxic mechanisms and roles by which killer cells can use Gzms to combat viral infections, and discuss the potential thereof for the development of novel therapies.
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