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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Perforin and granzymes: function, dysfunction and human pathology
Ilia Voskoboinik,Ilia Voskoboinik,James C. Whisstock,James C. Whisstock,Joseph A. Trapani,Joseph A. Trapani +5 more
TL;DR: The current understanding of the structural, cellular and clinical aspects of perforin and granzyme biology is discussed, beginning to define and understand a range of human diseases that are associated with a failure to deliver active per forin to target cells.
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The immunological synapse: A molecular machine controlling T cell activation
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Intracellular Delivery by Membrane Disruption: Mechanisms, Strategies, and Concepts.
TL;DR: Techniques for membrane disruption-based intracellular delivery from 1911 until the present achieve rapid, direct, and universal delivery of almost any cargo molecule or material that can be dispersed in solution.
Journal ArticleDOI
Cytotoxic T Cells Use Mechanical Force to Potentiate Target Cell Killing.
Roshni Basu,Benjamin M. Whitlock,Julien Husson,Audrey Le Floc’h,Weiyang Jin,Alon Oyler-Yaniv,Farokh Dotiwala,Grégory Giannone,Claire Hivroz,Nicolas Biais,Judy Lieberman,Lance C. Kam,Morgan Huse +12 more
TL;DR: An unappreciated physical dimension to lymphocyte function is revealed and cells use mechanical forces to control the activity of outgoing chemical signals and data indicate that CTLs coordinate perforin release and force exertion in space and time.
Journal ArticleDOI
Membrane Repair: Mechanisms and Pathophysiology
Sandra T. Cooper,Paul L. McNeil +1 more
TL;DR: Collective evidence reveals membrane repair employs primitive yet robust molecular machinery, such as vesicle fusion and contractile rings, processes evolutionarily honed for simplicity and success.
References
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