Cathepsin G, and not the asparagine-specific endoprotease, controls the processing of myelin basic protein in lysosomes from human B lymphocytes.
The asparagine-specific endoprotease (AEP) controls lysosomal processing of the potential autoantigen myelin basic protein (MBP) by human B lymphoblastoid cells, a feature implicated in the immunopathogenesis of multiple sclerosis. In this study, we demonstrate that freshly isolated human B lymphocytes lack significant AEP activity and that cleavage by AEP is dispensable for proteolytic processing of MBP in this type of cell. Instead, cathepsin (Cat) G, a serine protease that is not endogenously synthesized by B lymphocytes, is internalized from the plasma membrane and present in lysosomes from human B cells where it represents a major functional constituent of the proteolytic machinery. CatG initialized and dominated the destruction of intact MBP by B cell-derived lysosomal extracts, degrading the immunodominant MBP epitope and eliminating both its binding to MHC class II and a MBP-specific T cell response. Degradation of intact MBP by CatG was not restricted to a lysosomal environment, but was also performed by soluble CatG. Thus, the abundant protease CatG might participate in eliminating the immunodominant determinant of MBP. Internalization of exogenous CatG represents a novel mechanism of professional APC to acquire functionally dominant proteolytic activity that complements the panel of endogenous lysosomal enzymes.
Burster
Timo
T
Department of Medicine II, University of Tübingen, Tübingen, Germany.
Beck
Alexander
A
Tolosa
Eva
E
Marin-Esteban
Viviana
V
Rötzschke
Olaf
O
Falk
Kirsten
K
Lautwein
Alfred
A
Reich
Michael
M
Brandenburg
Jens
J
Schwarz
Gerold
G
Wiendl
Heinz
H
Melms
Arthur
A
Lehmann
Rainer
R
Stevanovic
Stefan
S
Kalbacher
Hubert
H
Driessen
Christoph
C
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000201:enzymology / Q000378:metabolism; D001216:Asparagine / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D056649:Cathepsin G; D002403:Cathepsins / Q000502:physiology*; D002460:Cell Line; D002461:Cell Line, Transformed; D002469:Cell Separation; D003546:Cysteine Endopeptidases / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D008213:Lymphocyte Activation / Q000276:immunology; D008239:Lysine / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000378:metabolism*; D010649:Phenylalanine / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D012694:Serine / Q000378:metabolism; D012697:Serine Endopeptidases; D000099240:Asparaginyl Endopeptidase
D001216:Asparagine; D056649:Cathepsin G; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D008239:Lysine; D004676:Myelin Basic Protein; D010649:Phenylalanine; D012694:Serine; D012697:Serine Endopeptidases; D000099240:Asparaginyl Endopeptidase; C534094:CTSG protein, human; C534096:Ctsg protein, mouse