title: Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis.
abstract: Perforin delivers granzymes to induce target-cell apoptosis. At high concentrations, perforin multimerizes in the plasma membrane to form pores. However, whether granzymes enter target cells via membrane pores is uncertain. Here we find that perforin at physiologically relevant concentrations and during cell-mediated lysis creates pores in the target-cell membrane, transiently allowing Ca(2+) and small dyes into the cell. The Ca(2+) flux triggers a wounded membrane-repair response in which internal vesicles, including lysosomes and endosomes, donate their membranes to reseal the damaged membrane. Perforin also triggers the rapid endocytosis of granzymes into large EEA-1-staining vesicles. The restoration of target-cell membrane integrity by triggering the repair response is necessary for target cells subjected to cytotoxic T lymphocyte attack to avoid necrosis and undergo the slower process of programmed cell death. Thus, the target cell actively participates in determining its own fate during cell-mediated death.
authors.affiliation: The CBR Institute for Biomedical Research, Boston, MA 02115, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Keefe
authors.forename: Lianfa
authors.initials: L
authors.lastname: Shi
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
authors.forename: Ramiro
authors.initials: R
authors.lastname: Massol
authors.forename: Francisco
authors.initials: F
authors.lastname: Navarro
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhausen
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D053804:Granzymes; D006801:Humans; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D018613:Microscopy, Confocal; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D020298:U937 Cells
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D002118:Calcium