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
More filters
Journal ArticleDOI
Solving the secretory acid sphingomyelinase puzzle: Insights from lysosome-mediated parasite invasion and plasma membrane repair.
TL;DR: The possibility that ASM release during lysosomal exocytosis, in response to various forms of stress, may represent a major source of the secretory form of this enzyme is discussed.
Patent
T-cell epitope identification
Robert A. Holt,Govinda Sharma +1 more
TL;DR: In this paper, a method for determining the identity of the epitopes recognized by T-cells is presented, which consists of expressing an encoded library of candidate epitope sequences in a recipient reporter cell capable of providing a detectable signal upon cytotoxic attack from a single cognate T-cell followed by contacting the reporter cells with Tcells of interest.
Journal ArticleDOI
Connexin-Mediated Signaling at the Immunological Synapse.
Andrés Tittarelli,Mariela Navarrete,María Alejandra Gleisner,Peter J. Gebicke-Haerter,Peter J. Gebicke-Haerter,Flavio Salazar-Onfray +5 more
TL;DR: An updated overview and analysis on the role and possible underlying mechanisms of Cx43 in IS signaling is provided and it is suggested that connexins, in particular connexin-43 (Cx43) hemichannels and/or gap junctions, regulate signaling events in different types of IS.
Journal ArticleDOI
Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity
TL;DR: It is clear that target cells are not passive bystanders to cell- mediated cytotoxicity and resistance mechanisms can significantly constrain immune cell-mediated killing, and the importance of tumour necrosis factor-related apoptosis-inducing ligand and resistance mechanism against this pathway is considered.
Journal ArticleDOI
The C-ETS2-TFEB Axis Promotes Neuron Survival under Oxidative Stress by Regulating Lysosome Activity
Shumin Ma,Zijun Fang,Wenwen Luo,Yunzhi Yang,Chenyao Wang,Qian Zhang,Huafei Wang,Huaiyong Chen,Chi Bun Chan,Zhixue Liu +9 more
TL;DR: It is shown that cell apoptosis is induced by oxidative stress and that lysosomes play an important role in cell survival under oxidative stress, and it is confirmed that TFEB protects cells from oxidative stress both in vitro and in vivo.
References
More filters
Journal ArticleDOI
The Immunological Synapse: A Molecular Machine Controlling T Cell Activation
Arash Grakoui,Shannon K. Bromley,Cenk Sumen,Mark M. Davis,Andrey S. Shaw,Paul M. Allen,Michael L. Dustin +6 more
TL;DR: Immunological synapse formation is now shown to be an active and dynamic mechanism that allows T cells to distinguish potential antigenic ligands and was a determinative event for T cell proliferation.
Journal ArticleDOI
Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology.
TL;DR: The acidity of intracellular compartments and the extracellular environment is crucial to various cellular processes, including membrane trafficking, protein degradation, bone resorption and sperm maturation, and the V-ATPases represent attractive and potentially highly specific drug targets.
Journal ArticleDOI
The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway.
Cecilia Bucci,Robert G. Parton,Ian H. Mather,Henk Stunnenberg,Kai Simons,Bernard Hoflack,Marino Zerial +6 more
TL;DR: It is concluded that rab5 is a rate-limiting component of the machinery regulating the kinetics of membrane traffic in the early endocytic pathway.
Journal ArticleDOI
Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells.
TL;DR: Results suggest that the vacuolar type H(+)-ATPase plays a pivotal role in acidification and protein degradation in the lysosomes in vivo.
Journal ArticleDOI
Perforin Gene Defects in Familial Hemophagocytic Lymphohistiocytosis
Susan E. Stepp,Dufourcq-Lagelouse R,Françoise Le Deist,Françoise Le Deist,Sadhna Bhawan,Stéphanie Certain,Porunelloor A. Mathew,Jan-Inge Henter,Michael J. Bennett,Alain Fischer,Alain Fischer,Geneviève de Saint Basile,Vinay Kumar +12 more
TL;DR: In this paper, the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients.
Related Papers (5)
The structural basis for membrane binding and pore formation by lymphocyte perforin
Ruby H. P. Law,Natalya Lukoyanova,Ilia Voskoboinik,Ilia Voskoboinik,Tom T. Caradoc-Davies,Katherine Baran,Michelle A. Dunstone,Michelle A. Dunstone,Michael E. D'Angelo,Elena V. Orlova,Fasséli Coulibaly,Sandra Verschoor,Kylie A. Browne,Annette Ciccone,Michael J. Kuiper,Phillip I. Bird,Joseph A. Trapani,Joseph A. Trapani,Helen R. Saibil,James C. Whisstock,James C. Whisstock +20 more