Saposins

Saposins are proteins (known so far are saposins A, B, C, and D) are small heat-stable molecules that are developed from the precursor protein prosaposin, a 70 kDa glycoprotein. The mature saposins, like prosaposin, activate various lysosomal hydrolases that are invoved in the metabolism of sphingolipids. All 4 saposins are structurally similar, with a central 6-cysteine and a conserved proline formation (Kishimoto Y et al. 1993).

Saposins are generated via their precursor protein prosaposin. The coding gene of the precursor protein prosaposin is located on chromosome 10. Prosaposin is synthesized as a molecule that is posttranslationally shortened and formed into a soluble product by glycolysis.

The proteins saposine-B and C play a particularly important role in the processing of lipid antigens. These proteins are capable of transferring lipids e.g. from a cell membrane to the CD1 complex (Sun Y et al. 2013).

Saposin B molecules aggregate to form soluble saposin-protein-lipid complexes that are able to directly load the CD1 protein, a process that is of central importance in CD1-associated antigen presentation.

Saposin C facilitates CD1-lipid loading in a slightly different way. Saposin C uses a stable membrane-associated topological structure to load CD1-directly with lipid antigens without formation of a soluble saposin-lipid complex.

Thus, saposins use different strategies to load CD1 complexes with lipid antigens. The development of different strategies demonstrates the pathophysiological importance of this antigen processing.

Saposin C deficiency leads to a rare variant of M.Gaucher (E75.2) and is based on a mutation in the prosaposin gene (PSAP). Functionally, this defect leads to an autophagic dysfunction (disturbance of the lysosomes' waste disposal function) and to an accumulation of non-degradable glucocerebrosides.

1. Kishimoto Y et al (1993) Saposins: structure, function, distribution, and molecular genetics. J Lipid Res 33:1255-1267.
2. León L et al (2012) Saposins utilize two strategies for lipid transfer and CD1 antigen presentation. Proc Natl Acad Sci U S A 109:4357-4364.
3. Sun Y et al (2013) Tissue-specific effects of saposin A and saposin B on glycosphingolipid degradation in mutant mice. Hum Mol Genet 22:2435-2450.
4. Tatti M et al (2013) Cathepsin-mediated regulation of autophagy in saposin C deficiency. Autophagy 9:241-243.