Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis.
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.
Tolosa
Eva
E
Neuroimmunology, Department of Neurology, Tübingen University Hospital, Auf der Morgenstelle 15, 72076 Tübingen, Germany. eva.tolosa@uni-tuebingen.de
Li
Weijie
W
Yasuda
Yoshiyuki
Y
Wienhold
Wolfgang
W
Denzin
Lisa K
LK
Lautwein
Alfred
A
Driessen
Christoph
C
Schnorrer
Petra
P
Weber
Ekkehard
E
Stevanovic
Stefan
S
Kurek
Raffael
R
Melms
Arthur
A
Bromme
Dieter
D
D000293:Adolescent; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry / Q000378:metabolism*; D015153:Blotting, Western; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D007834:Lasers; D051379:Mice; D009157:Myasthenia Gravis / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000378:metabolism*; D014018:Tissue Distribution
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D012333:RNA, Messenger; D011994:Recombinant Proteins; C045084:invariant chain; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C028217:cathepsin S; C117627:CTSV protein, human