Saposin B binds and transfers phospholipids

Ciaffoni, Fiorella; Tatti, Massimo; Boe, Alessandra; Salvioli, Rosa; Fluharty, Arvan L.; Sonnino, Sandro; Vaccaro, Anna Maria

doi:10.1194/jlr.m500547-jlr200

Cited by 32 publications

(39 citation statements)

References 45 publications

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“…There have been many reports that CD1d can be loaded with phospholipids and present them to T cells (30,33,39,40). Saposin B, despite the fact it was initially identified as a sphingolipid activator protein, also binds and transfers phospholipids (41). It binds to some phospholipids with comparable or even higher affinities than it binds glycosphingolipids (34).…”

Section: Saposin B Most Efficiently Enhances Cd1d Lipid Presentation mentioning

confidence: 99%

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Yuan

Tsang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

102

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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 α-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 α-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.

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Section: Saposin B Most Efficiently Enhances Cd1d Lipid Presentation mentioning

confidence: 99%

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Yuan

Tsang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Our findings suggest that the activity of CD1e is more similar to that of Sap-B. Indeed, CD1e selectively transfers diacylated PIM from donor to acceptor liposomes, resembling GM2AP and Sap-B (12,22,25) without affecting vesicle structure and membrane fusion, which are instead hallmarks of Sap-C and Sap-D (23,26). However, CD1e and Sap-B do not have completely overlapping functions as suggested by the finding that CD1e is absolutely required for PIM 6 antigenicity (7).…”

Section: Discussionmentioning

confidence: 67%

“…Saposins have been shown to increase lipid substrate accessibility for enzymatic digestion by either (i) membrane disorganization as for Sap-C or (ii) lipid transfer properties from membrane-to-membrane or from membrane to protein as for Sap-B (12).…”

Section: Cd1e Assists Mannosidase In Processing Of Specific Acylmentioning

confidence: 99%

“…They mediate the interaction between the water-soluble exohydrolase and their membrane-embedded glycolipid substrates at the lipidwater interface. Saposins may act via two distinct mechanisms, including membrane destabilization (11) and direct binding and transferring of monomeric lipids (12). In the context of CD1 proteins, saposins facilitate binding of ␣-GalCer to CD1d (13), with Sap-B involved in the loading of CD1d with lipid antigens (14,15), and Sap-C involved in the loading of CD1b with mycobacterial lipoarabinomannan antigen (16).…”

mentioning

confidence: 99%

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Deciphering the Role of CD1e Protein in Mycobacterial Phosphatidyl-myo-inositol Mannosides (PIM) Processing for Presentation by CD1b to T Lymphocytes

Paepe

Layre

Giacometti

et al. 2012

Journal of Biological Chemistry

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Background: To become antigenic, mycobacterial hexamannosylated phosphatidyl-myo-inositol (PIM 6 ) undergo CD1e-assisted ␣-mannosidase processing. Results: Measuring membrane-to-membrane PIM transfer, CD1e selectively transferred diacylated PIM species in accordance with the fact that liposome-inserted di-acylated PIM 6 were the only PIM species digested into antigenic molecules by ␣-mannosidase. Conclusion: CD1e assists PIM processing through its lipid transfer protein property. Significance: This study reveals the molecular mechanisms by which CD1e contributes to lipid immunoediting.

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“…The observation that basal but not inflammatory autoreactivity is maintained in the absence of prosaposin expression suggests that a qualitative and quantitative difference in the lipid profile exists between uninfected and infected THP-1. For example, basal autoreactivity to phospholipids, such as phosphatidylinositol, has been demonstrated for murine iNKT cells (46), and this may not be prosaposin-dependent despite the ability of saposin B to bind and transfer phospholipids in vitro at acidic pH (47). Furthermore, the saposin-dependence of peroxisome-derived lipids (48) or of lysophospholipids (49), which stimulate thymic and peripheral iNKT cells, remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Saposins modulate human invariant Natural Killer T cells self-reactivity and facilitate lipid exchange with CD1d molecules during antigen presentation

Salio

Ghadbane

Dushek³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Lipid transfer proteins, such as molecules of the saposin family, facilitate extraction of lipids from biological membranes for their loading onto CD1d molecules. Although it has been shown that prosaposin-deficient mice fail to positively select invariant natural killer T (iNKT) cells, it remains unclear whether saposins can facilitate loading of endogenous iNKT cell agonists in the periphery during inflammatory responses. In addition, it is unclear whether saposins, in addition to loading, also promote dissociation of lipids bound to CD1d molecules. To address these questions, we used a combination of cellular assays and demonstrated that saposins influence CD1d-restricted presentation to human iNKT cells not only of exogenous lipids but also of endogenous ligands, such as the self-glycosphingolipid β-glucopyranosylceramide, up-regulated by antigen-presenting cells following bacterial infection. Furthermore, we demonstrated that in human myeloid cells CD1d-loading of endogenous lipids after bacterial infection, but not at steady state, requires trafficking of CD1d molecules through an endo-lysosomal compartment. Finally, using BIAcore assays we demonstrated that lipid-loaded saposin B increases the offrate of lipids bound to CD1d molecules, providing important insights into the mechanisms by which it acts as a "lipid editor," capable of fine-tuning loading and unloading of CD1d molecules. These results have important implications in understanding how to optimize lipid-loading onto antigen-presenting cells, to better harness iNKT cells central role at the interface between innate and adaptive immunity. autoreactivity | inflammation | innate immunity | lipid binding proteins

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Saposin B binds and transfers phospholipids

Cited by 32 publications

References 45 publications

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Deciphering the Role of CD1e Protein in Mycobacterial Phosphatidyl-myo-inositol Mannosides (PIM) Processing for Presentation by CD1b to T Lymphocytes

Saposins modulate human invariant Natural Killer T cells self-reactivity and facilitate lipid exchange with CD1d molecules during antigen presentation

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