Soluble beta 2-microglobulin-free class I heavy chains are released from the surface of activated and leukemia cells by a metalloprotease.
Regulation of the expression of major histocompatibility complex (MHC) class I heavy chains not associated with beta 2-microglobulin (beta 2m) on freshly isolated and in vitro cultured human B and T leukemia cells was analyzed. These beta 2m-free class I heavy chains originate from surface beta 2m-associated MHC class I molecules and are expressed as integral membrane glycoproteins on activated, but not resting, cells. We found that the levels of beta 2m-free class I heavy chains can be regulated by proteolytic cleavage and release into the medium of soluble molecules containing the extracellular domains. The release is mediated by a Zn(2+)-dependent, membrane-bound metalloprotease that does not cleave HLA-DR, CD4, and CD71 surface receptors and can be activated by phorbol myristate acetate. Specific cleavage by the metalloprotease occurs at a site close to the papain cleavage site in the alpha 3 domain of class I heavy chains. This site is not accessible to the metalloprotease in beta 2m-associated MHC class I molecules. The dissociation of beta 2m-associated MHC class I molecules and subsequent cleavage of beta 2m-free class I heavy chains may be partially responsible for controlling the levels of MHC class I molecules on the surface of activated cells.
Demaria
S
S
Laboratory of Molecular Immunology, Public Health Research Institute, New York, New York 10016.
Schwab
R
R
Gottesman
S R
SR
Bushkin
Y
Y
D015703:Antigens, CD / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D015448:Leukemia, B-Cell / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000276:immunology*; D015458:Leukemia, T-Cell / Q000276:immunology*; D046911:Macromolecular Substances; D008666:Metalloendopeptidases / Q000378:metabolism*; D010618:Phenanthrolines / Q000494:pharmacology; D011990:Receptors, Transferrin; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000494:pharmacology; D001613:beta 2-Microglobulin / Q000302:isolation & purification*
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D015704:CD4 Antigens; C068126:CD71 antigen; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; D046911:Macromolecular Substances; D010618:Phenanthrolines; D011990:Receptors, Transferrin; D001613:beta 2-Microglobulin; D008666:Metalloendopeptidases; D015032:Zinc; D013755:Tetradecanoylphorbol Acetate