Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis
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Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. / Tolosa, Eva; Li, Weijie; Yasuda, Yoshiyuki; Wienhold, Wolfgang; Denzin, Lisa K; Lautwein, Alfred; Driessen, Christoph; Schnorrer, Petra; Weber, Ekkehard; Stevanovic, Stefan; Kurek, Raffael; Melms, Arthur; Bromme, Dieter.
in: J CLIN INVEST, Jahrgang 112, Nr. 4, 01.08.2003, S. 517-26.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis
AU - Tolosa, Eva
AU - Li, Weijie
AU - Yasuda, Yoshiyuki
AU - Wienhold, Wolfgang
AU - Denzin, Lisa K
AU - Lautwein, Alfred
AU - Driessen, Christoph
AU - Schnorrer, Petra
AU - Weber, Ekkehard
AU - Stevanovic, Stefan
AU - Kurek, Raffael
AU - Melms, Arthur
AU - Bromme, Dieter
PY - 2003/8/1
Y1 - 2003/8/1
N2 - Stepwise degradation of the invariant chain (Ii) is required for the binding of antigenic peptides to MHC class II molecules. Cathepsin (Cat) L in the murine thymus and Cat S in peripheral APCs have both been implicated in the last step of Ii degradation that gives rise to the class II-associated invariant chain peptides (CLIP). Cat V has been recently described as highly homologous to Cat L and exclusively expressed in human thymus and testis, but with no mouse orthologue. We report that Cat V is the dominant cysteine protease in cortical human thymic epithelial cells, while Cat L and Cat S seem to be restricted to dendritic and macrophage-like cells. Active Cat V in thymic lysosomal preparations was demonstrated by active-site labeling. Recombinant Cat V was capable of converting Ii into CLIP efficiently, suggesting that Cat V is the protease that controls the generation of alphabeta-CLIP complexes in the human thymus, in analogy to Cat L in mouse. Comparison of Cat V expression between thymi from patients with myasthenia gravis and healthy controls revealed a significantly higher expression level in the pathological samples, suggesting a potential involvement of this protease in the immunopathogenesis of myasthenia gravis, an autoimmune disease almost invariably associated with thymic pathology.
AB - Stepwise degradation of the invariant chain (Ii) is required for the binding of antigenic peptides to MHC class II molecules. Cathepsin (Cat) L in the murine thymus and Cat S in peripheral APCs have both been implicated in the last step of Ii degradation that gives rise to the class II-associated invariant chain peptides (CLIP). Cat V has been recently described as highly homologous to Cat L and exclusively expressed in human thymus and testis, but with no mouse orthologue. We report that Cat V is the dominant cysteine protease in cortical human thymic epithelial cells, while Cat L and Cat S seem to be restricted to dendritic and macrophage-like cells. Active Cat V in thymic lysosomal preparations was demonstrated by active-site labeling. Recombinant Cat V was capable of converting Ii into CLIP efficiently, suggesting that Cat V is the protease that controls the generation of alphabeta-CLIP complexes in the human thymus, in analogy to Cat L in mouse. Comparison of Cat V expression between thymi from patients with myasthenia gravis and healthy controls revealed a significantly higher expression level in the pathological samples, suggesting a potential involvement of this protease in the immunopathogenesis of myasthenia gravis, an autoimmune disease almost invariably associated with thymic pathology.
KW - Adolescent
KW - Animals
KW - Antigens, Differentiation, B-Lymphocyte
KW - Blotting, Western
KW - Cathepsin L
KW - Cathepsins
KW - Child
KW - Child, Preschool
KW - Cysteine Endopeptidases
KW - Dose-Response Relationship, Drug
KW - Histocompatibility Antigens Class II
KW - Humans
KW - Immunohistochemistry
KW - Infant
KW - Infant, Newborn
KW - Lasers
KW - Mice
KW - Myasthenia Gravis
KW - Peptides
KW - RNA, Messenger
KW - Recombinant Proteins
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Thymus Gland
KW - Tissue Distribution
U2 - 10.1172/JCI18028
DO - 10.1172/JCI18028
M3 - SCORING: Journal article
C2 - 12925692
VL - 112
SP - 517
EP - 526
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 4
ER -