title: A family with Papillon-Lefevre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity.
abstract: Activation of granzyme B, a key cytolytic effector molecule of natural killer (NK) cells, requires removal of an N-terminal pro-domain. In mice, cathepsin C is required for granzyme processing and normal NK cell cytolytic function, whereas in patients with Papillon-Lefèvre syndrome (PLS), loss-of-function mutations in cathepsin C do not affect lymphokine activated killer (LAK) cell function. Here we demonstrate that resting PLS NK cells do have a cytolytic defect and fail to induce the caspase cascade in target cells. NK cells from these patients contain inactive granzyme B, indicating that cathepsin C is required for granzyme B activation in unstimulated human NK cells. However, in vitro activation of PLS NK cells with interleukin-2 restores cytolytic function and granzyme B activity by a cathepsin C-independent mechanism. This is the first documented example of a human mutation affecting granzyme B activity and highlights the importance of cathepsin C in human NK cell function.
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Josephine L
authors.initials: JL
authors.lastname: Meade
authors.forename: Erika A
authors.initials: EA
authors.lastname: de Wynter
authors.forename: Peter
authors.initials: P
authors.lastname: Brett
authors.forename: Saghira Malik
authors.initials: SM
authors.lastname: Sharif
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Markham
authors.forename: Graham P
authors.initials: GP
authors.lastname: Cook
mesh_terms: D000818:Animals; D020789:Cathepsin C / Q000235:genetics / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation; D005260:Female; D053804:Granzymes; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D008297:Male; D051379:Mice; D009154:Mutation; D010214:Papillon-Lefevre Disease / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D020789:Cathepsin C; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases