title: Soluble nonclassical HLA generated by the metalloproteinase pathway.
abstract: Soluble human leukocyte antigens (HLA-A, -B, and -C) proteins can be generated by a membrane-bound metalloproteinase (MPase). The MPase-mediated pathway produces soluble nonconformed HLA proteins susceptible to further degradation, and also HLA proteins with high affinity peptides stable at physiologic temperatures. Accessibility of classical HLA to the MPase cleavage inversely correlates with stability of heavy chain (HC) interactions with beta2-microglobulin (beta(2)m). Whether a MPase is involved in release of soluble nonclassical HLA or CD1 proteins is unknown. We have investigated this question with transfectants expressing full-length HLA proteins. Native surface HLA-E and -G complexes, similar to HLA-A2, were unstable at low pH and dissociated giving rise to beta(2)m-free HC. Furthermore, HLA-E and -G proteins, similar to HLA-A2, were readily released from cell surface into supernatants as soluble 37-kilodalton beta(2)m-free HC. However, the stability of surface CD1d complexes was not affected by pH changes and no soluble CD1d was detected. Because beta(2)m-free CD1d HC were expressed on cells, the lack of cleaved soluble products cannot be explained by high stability of native complexes. Instead, absence of a CD1d-specific MPase in these cells or its impaired interactions with substrate HC may be responsible.
authors.affiliation: Laboratory of Molecular Immunology, Public Health Research Institute, Newark, NJ, USA.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Dong
authors.forename: Jaroslava
authors.initials: J
authors.lastname: Lieskovska
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Kedrin
authors.forename: Steven
authors.initials: S
authors.lastname: Porcelli
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bushkin
mesh_terms: D018949:Antigens, CD1 / Q000378:metabolism; D055610:Antigens, CD1d; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology / Q000276:immunology; D006680:HLA Antigens / Q000737:chemistry / Q000378:metabolism*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D012995:Solubility; D014162:Transfection; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000378:metabolism; D000097625:HLA-E Antigens
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D008666:Metalloendopeptidases; D001613:beta 2-Microglobulin; D000097625:HLA-E Antigens; C526877:CD1D protein, human