Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis.
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.
Keefe
Dennis
D
The CBR Institute for Biomedical Research, Boston, MA 02115, USA.
Shi
Lianfa
L
Feske
Stefan
S
Massol
Ramiro
R
Navarro
Francisco
F
Kirchhausen
Tomas
T
Lieberman
Judy
J
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
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D002118:Calcium