Endosomal aspartic proteinases are required for invariant-chain processing.
Immunogenic peptides are displayed in the context of class II histocompatibility proteins on the surface of antigen-presenting cells. Class II alpha and beta subunits bind the invariant chain (I-chain), a transmembrane glycoprotein which must dissociate prior to peptide presentation. Proteolytic release of I-chain in an acidic compartment is followed by class II alpha beta surface expression. Two distinct proteinases sequentially catalyze I-chain dissociation in B-lymphoblastoid cell lines. An aspartic proteinase initiates processing whereas a cysteine proteinase catalyzes the final stages of I-chain release. Inactivation of these enzymes prevents class II alpha beta maturation, demonstrating that acidic proteinases are essential for the generation of functional class II complexes. I-chain processing was localized to a dense endosomal compartment, suggesting this is the first site where class II alpha beta become accessible to peptides. I-chain fragments complexed with class II alpha beta accumulate in dense endosomes of B-lymphoblastoid cells treated with cysteine proteinase inhibitors. A signal for endosomal retention/targeting present in the cytoplasmic tail of these fragments may sequester class II alpha beta in this compartment until I-chain processing is complete.
Marić
M A
MA
Immunology Program, Virginia Mason Research Center, Seattle, WA 98101.
Taylor
M D
MD
Blum
J S
JS
D000944:Antigens, Differentiation, B-Lymphocyte; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001402:B-Lymphocytes / Q000201:enzymology* / Q000648:ultrastructure; D002460:Cell Line; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D015388:Organelles / Q000201:enzymology*; D011499:Protein Processing, Post-Translational
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C045084:invariant chain; D016282:Aspartic Acid Endopeptidases