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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Journal ArticleDOI
Endosomal Escape of Bioactives Deployed via Nanocarriers: Insights Into the Design of Polymeric Micelles
Adeel Masood Butt,Nabiha Abdullah,Nur Najihah Izzati binti Mat Rani,Naveed Ahmad,Mohd Cairul Iqbal Mohd Amin +4 more
TL;DR: The mechanisms by which nanocarriers are endocytosed, the mechanisms of endosomal escape, and more importantly, the strategies that can be and have been employed for their escape from the endosomes are summarized.
Journal ArticleDOI
Recycling endosomes in human cytotoxic T lymphocytes constitute an auxiliary intracellular trafficking pathway for newly synthesized perforin.
TL;DR: The recycling endosome pathway may serve as an auxiliary intracellular route for the delivery of new perforin to an immunologic synapse in order to perpetuate a cytotoxic response.
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Greek Fire, Poison Arrows, and Scorpion Bombs: How Tumor Cells Defend Against the Siege Weapons of Cytotoxic T Lymphocytes
TL;DR: It is proposed that understanding and targeting multiple steps of the attack/defense process will be instrumental to enhance the efficacy of CTL anti-tumor activity and meet the outstanding challenges in clinical immunotherapy.
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Actin remodeling and vesicular trafficking at the tumor cell side of the immunological synapse direct evasion from cytotoxic lymphocytes.
Andrea Michela Biolato,Liza Filali,Hannah Wurzer,Céline Hoffmann,Ernesto Gargiulo,Salvatore Valitutti,Clément Thomas +6 more
TL;DR: In this article, the authors review current knowledge of actin and vesicle dynamics in cancer cells during cytotoxic lymphocyte attack and tumor immune evasion and show that such changes are closely intertwined with evasion from immune destruction.
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Ultrarapid lytic granule release from CTLs activates Ca<sup>2+</sup>-dependent synaptic resistance pathways in melanoma cells
TL;DR: In this paper , the authors used single-cell time-lapse microscopy to offer high spatiotemporal resolution analyses of subcellular events in melanoma cells upon CTL attack.
References
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Perforin Gene Defects in Familial Hemophagocytic Lymphohistiocytosis
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