Soluble nonclassical HLA generated by the metalloproteinase pathway

Yuzhi Dong, Jaroslava Lieskovska, Dmitriy Kedrin, Steven Porcelli, Ofer Mandelboim, Yuri Bushkin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


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 β2-microglobulin (β2M). Whether a MPase is involved in release of soluble non-classical 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 β2m-free HC. Furthermore, HLA-E and -G proteins, similar to HLA-A2, were readily released from cell surface into supernatants as soluble 37-kilodalton β2m-free HC. However, the stability of surface CD1d complexes was not affected by pH changes and no soluble CD1d was detected. Because β2m-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.

Original languageAmerican English
Pages (from-to)802-810
Number of pages9
JournalHuman Immunology
Issue number8
StatePublished - 1 Aug 2003

Bibliographical note

Funding Information:
This work was supported by NIH grants AI 45761 and HL 59835 (Y. B.), AI 45889 (S. P.), and grant 153/00 from the Israeli Science Foundation (O. M.).


  • CD1d
  • Metalloproteinase
  • Soluble nonclassical HLA
  • β-microglobulin


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