Cytotoxic cell granule-mediated apoptosis: perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation.
The mechanism underlying perforin (PFN)-dependent delivery of apoptotic granzymes during cytotoxic cell granule-mediated death remains speculative. Granzyme B (GrB) and perforin were found to coexist as multimeric complexes with the proteoglycan serglycin (SG) in cytotoxic granules, and cytotoxic cells were observed to secrete exclusively macromolecular GrB-SG. Contrary to the view that PFN acts as a gateway for granzymes through the plasma membrane, monomeric PFN and, strikingly, PFN-SG complexes were shown to mediate cytosolic delivery of macromolecular GrB-SG without producing detectable plasma membrane pores. These results indicate that granule-mediated apoptosis represents a phenomenon whereby the target cell perceives granule contents as a multimeric complex consisting of SG, PFN, and granzymes, which are, respectively, the scaffold, translocator, and targeting/informational components of this modular delivery system.
Metkar
Sunil S
SS
Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA.
Wang
Baikun
B
Aguilar-Santelises
Miguel
M
Raja
Srikumar M
SM
Uhlin-Hansen
Lars
L
Podack
Eckhard
E
Trapani
Joseph A
JA
Froelich
Christopher J
CJ
D017209:Apoptosis; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology*; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000473:pathology*; D004705:Endocytosis; D053804:Granzymes; D006801:Humans; D006868:Hydrolysis; D008562:Membrane Glycoproteins / Q000378:metabolism*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000378:metabolism*
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases