Perforin activity at membranes leads to invaginations and vesicle formation

The cytotoxic cell granule secretory pathway is essential for immune defence. How the pore-forming protein perforin (PFN) facilitates the cytosolic delivery of granule-associated proteases (granzymes) remains enigmatic. Here we show that PFN is able to induce invaginations and formation of complete...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2011-12, Vol.108 (52), p.21016-21021
Main Authors: Praper, Tilen, Sonnen, Andreas F.-P, Kladnik, Aleš, Andrighetti, Alberto O, Viero, Gabriella, Morris, Keith J, Volpi, Emanuela, Lunelli, Lorenzo, Serra, Mauro Dalla, Froelich, Christopher J, Gilbert, Robert J. C, Anderluh, Gregor
Format: Article
Language:English
Subjects:
Antibodies
Apoptosis
Biological Sciences
calcium
Capacitance
Cell Membrane - metabolism
Cell membranes
Cryoelectron Microscopy
Curvature
Cytotoxicity
Dextrans
Endocytosis - physiology
Granzymes - metabolism
Humans
Immunity, Innate - physiology
Jurkat Cells
Lipids
Membranes
Microscopy, Fluorescence
Natural killer cells
Oligomers
P branes
Perforin - immunology
Perforin - metabolism
Perforin - physiology
proteinases
Proteins
secretory granules
Secretory Vesicles - metabolism
Signal transduction
surface area
T lymphocytes
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Summary:The cytotoxic cell granule secretory pathway is essential for immune defence. How the pore-forming protein perforin (PFN) facilitates the cytosolic delivery of granule-associated proteases (granzymes) remains enigmatic. Here we show that PFN is able to induce invaginations and formation of complete internal vesicles in giant unilamellar vesicles. Formation of internal vesicles depends on native PFN and calcium and antibody labeling shows the localization of PFN at the invaginations. This vesiculation is recapitulated in large unilamellar vesicles and in this case PFN oligomers can be seen associated with the necks of the invaginations. Capacitance measurements show PFN is able to increase a planar lipid membrane surface area in the absence of pore formation, in agreement with the ability to induce invaginations. Finally, addition of PFN to Jurkat cells causes the formation of internal vesicles prior to pore formation. PFN is capable of triggering an endocytosis-like event in addition to pore formation, suggesting a new paradigm for its role in delivering apoptosis-inducing granzymes into target cells.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1107473108