title: Mannose 6 phosphorylation of lysosomal enzymes controls B cell functions.
abstract: Antigen processing and presentation and cytotoxic targeting depend on the activities of several lysosomal enzymes that require mannose 6-phosphate (M6P) sorting signals for efficient intracellular transport and localization. In this paper, we show that mice deficient in the formation of M6P residues exhibit significant loss of cathepsin proteases in B cells, leading to lysosomal dysfunction with accumulation of storage material, impaired antigen processing and presentation, and subsequent defects in B cell maturation and antibody production. The targeting of lysosomal and granular enzymes lacking M6P residues is less affected in dendritic cells and T cells and sufficient for maintenance of degradative and lytic functions. M6P deficiency also impairs serum immunoglobulin levels and antibody responses to vaccination in patients. Our data demonstrate the critical role of M6P-dependent transport routes for B cell functions in vivo and humoral immunity in mice and human.
authors.affiliation: Department of Biochemistry, Children's Hospital; Department of Electron Microscopy, Center for Molecular Neurobiology; and Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany Department of Pediatrics, Osaka University Graduate School of Medicine, 5650871 Suita, Osaka, Japan otomo@ped.med.osaka-u.ac.jp braulke@uke.de.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otomo
authors.affiliation: Department of Biochemistry, Children's Hospital; Department of Electron Microscopy, Center for Molecular Neurobiology; and Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.affiliation: Department of Biochemistry, Children's Hospital; Department of Electron Microscopy, Center for Molecular Neurobiology; and Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kollmann
authors.affiliation: Department of Biochemistry, Children's Hospital; Department of Electron Microscopy, Center for Molecular Neurobiology; and Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Valéa
authors.initials: V
authors.lastname: Schumacher
authors.affiliation: Department of Biochemistry, Children's Hospital; Department of Electron Microscopy, Center for Molecular Neurobiology; and Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Muschol
authors.affiliation: Department of Biochemistry, Children's Hospital; Department of Electron Microscopy, Center for Molecular Neurobiology; and Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Tolosa
authors.affiliation: Department of Biochemistry, Children's Hospital; Department of Electron Microscopy, Center for Molecular Neurobiology; and Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Mittrücker
authors.affiliation: Department of Biochemistry, Children's Hospital; Department of Electron Microscopy, Center for Molecular Neurobiology; and Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany otomo@ped.med.osaka-u.ac.jp braulke@uke.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000378:metabolism; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008360:Mannosephosphates / Q000378:metabolism*; D008822:Mice, Transgenic; D009081:Mucolipidoses / Q000201:enzymology / Q000276:immunology; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics
chemical_list: D000941:Antigens; D008360:Mannosephosphates; C027693:mannose-6-phosphate; D017855:Transferases (Other Substituted Phosphate Groups); C548056:GNPTAB protein, mouse; D010447:Peptide Hydrolases