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Abstract
CD1d molecules bind lipid antigens in the endocytic pathway, and access to the pathway is important for the development of CD1d-restricted natural killer T (NKT) cells. Saposins, derived from a common precursor, prosaposin, are small, heat-stable lysosomal glycoproteins required for lysosomal degradation of sphingolipids. Expression of prosaposin is required for efficient lipid binding and recognition of human CD1d molecules by NKT cells. Despite high sequence homology among the four saposins, they have different specificities for lipid substrates and different mechanisms of action. To determine the saposins involved in promoting lipid binding to CD1d, we expressed prosaposin deletion mutants lacking individual saposins in prosaposin-negative, CD1d-positive cells. No individual saposin proved to be absolutely essential, but the absence of saposin B resulted in the lowest recognition of alpha-galactosylceramide by NKT cells. When recombinant exogenous saposins were added to the prosaposin-negative cells, saposin B was the most efficient in restoring CD1d recognition. Saposin B was also the most efficient in mediating alpha-galactosylceramide binding to recombinant plate-bound CD1d and facilitating NKT cell activation. Saposin B could also mediate lipid binding to soluble CD1d molecules in a T cell-independent assay. The optimal pH for saposin B-mediated lipid binding to CD1d, pH 6, is higher than that of lysosomes, suggesting that saposin B may facilitate lipid binding to CD1d molecules throughout the endocytic pathway.
Original language | English |
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Pages (from-to) | 5551-5556 |
Number of pages | 6 |
Journal | National Academy of Sciences. Proceedings |
Volume | 104 |
Issue number | 13 |
DOIs | |
Publication status | Published - 27 Mar 2007 |
Keywords
- antigen processing
- lipid transfer proteins
- natural killer T cells
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Dive into the research topics of 'Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules'. Together they form a unique fingerprint.Projects
- 1 Finished
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Modulation of Immune Responses by aGalCer Analogues Through Differential Activation of CD1d-restricted NKT Cells
Besra, D. (Principal Investigator) & Lammas, T. (Co-Investigator)
1/06/05 → 30/11/09
Project: Research Councils