title: Cytotoxic cell granule-mediated apoptosis: perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation.
abstract: 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.
authors.affiliation: Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA.
authors.forename: Sunil S
authors.initials: SS
authors.lastname: Metkar
authors.forename: Baikun
authors.initials: B
authors.lastname: Wang
authors.forename: Miguel
authors.initials: M
authors.lastname: Aguilar-Santelises
authors.forename: Srikumar M
authors.initials: SM
authors.lastname: Raja
authors.forename: Lars
authors.initials: L
authors.lastname: Uhlin-Hansen
authors.forename: Eckhard
authors.initials: E
authors.lastname: Podack
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Froelich
mesh_terms: 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*
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases