title: Lysosomal cysteine and aspartic proteases are heterogeneously expressed and act redundantly to initiate human invariant chain degradation.
abstract: Presentation of Ag by class II MHC is regulated by lysosomal proteases that not only destroy the class II invariant chain (Ii) chaperone but also generate the peptide Ag that is loaded onto the class II MHC dimer. We sought to determine the extent to which asparagine endopeptidase (AEP) influences human Ag and Ii processing. Our data confirm the constructive function of AEP in tetanus toxoid processing, but they are discordant with findings that suggest a destructive role for AEP in processing of the immunodominant myelin basic protein epitope. Furthermore, we observed no effect on invariant chain processing following AEP inhibition for several distinct allelic variants of human class II MHC products. We find that cysteine and aspartic proteases, as well as AEP, can act redundantly to initiate Ii processing. We detected considerable variation in lysosomal activity between different EBV-transformed B cell lines, but these differences do not result in altered regulation of invariant chain catabolism. We propose that, as for bound peptide Ag, the identity of the lysosomal enzyme that initiates invariant chain cleavage is dependent on the class II MHC allelic variants expressed.
authors.affiliation: Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Costantino
authors.forename: Howard C
authors.initials: HC
authors.lastname: Hang
authors.forename: Sally C
authors.initials: SC
authors.lastname: Kent
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D002999:Clone Cells; D018920:Coculture Techniques; D003546:Cysteine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D018740:Genetic Heterogeneity; D006681:HLA-D Antigens / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D006681:HLA-D Antigens; D000949:Histocompatibility Antigens Class II; D011480:Protease Inhibitors; C045084:invariant chain; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases