title: Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis.
abstract: The serine proteinase granzyme B is crucial for the rapid induction of target cell apoptosis by cytotoxic T cells. Granzyme B was recently demonstrated to enter cells in a perforin-independent manner, thus predicting the existence of a cell surface receptor(s). We now present evidence that this receptor is the cation-independent mannose 6-phosphate/insulin-like growth factor receptor (CI-MPR). Inhibition of the granzyme B-CI-MPR interaction prevented granzyme B cell surface binding, uptake, and the induction of apoptosis. Significantly, expression of the CI-MPR was essential for cytotoxic T cell-mediated apoptosis of target cells in vitro and for the rejection of allogeneic cells in vivo. These results suggest a novel target for immunotherapy and a potential mechanism used by tumors for immune evasion.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Motyka
authors.forename: G
authors.initials: G
authors.lastname: Korbutt
authors.forename: M J
authors.initials: MJ
authors.lastname: Pinkoski
authors.forename: J A
authors.initials: JA
authors.lastname: Heibein
authors.forename: A
authors.initials: A
authors.lastname: Caputo
authors.forename: M
authors.initials: M
authors.lastname: Hobman
authors.forename: M
authors.initials: M
authors.lastname: Barry
authors.forename: I
authors.initials: I
authors.lastname: Shostak
authors.forename: T
authors.initials: T
authors.lastname: Sawchuk
authors.forename: C F
authors.initials: CF
authors.lastname: Holmes
authors.forename: J
authors.initials: J
authors.lastname: Gauldie
authors.forename: R C
authors.initials: RC
authors.lastname: Bleackley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001667:Binding, Competitive / Q000187:drug effects; D017690:Cell Transplantation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism; D053804:Granzymes; D006801:Humans; D020287:In Situ Nick-End Labeling; D019169:Jurkat Cells; D007668:Kidney / Q000276:immunology; D007739:L Cells; D008360:Mannosephosphates / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D017527:Receptor, IGF Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism* / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; C027693:mannose-6-phosphate; D010744:Phosphoric Monoester Hydrolases; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases