Sphingolipid activator proteins: proteins with complex functions in lipid degradation and skin biogenesis

Abstract

Sphingolipid activator proteins (SAPs or saposins) are essential cofactors for the lysosomal degradation of membrane-anchored sphingolipids. Four of the five known proteins of this class, SAPs A--D, derive from a single precursor protein and show high homology, whereas the fifth protein, GM2AP, is larger and displays a different secondary structure. Although the main function of all five proteins is assumed to lie in the activation of lipid degradation, their specificities and modes of action seem to differ considerably. It has recently been demonstrated that the action of the proteins is highly enhanced by the presence of acidic lipids in the target membranes. These results have some interesting implications for the topology of lysosomal degradation of lipids and may provide new insights into the function of these interesting proteins, which are ubiquitously expressed in the different tissues of the body. Recent studies indicated that the SAPs play an important role in the biogenesis of the epidermal water barrier, which has been demonstrated by the analysis of the skin phenotype displayed by SAP-knockout mice. The results obtained so far have led to some new insights into the formation of the epidermal water permeability barrier and may lead to a better understanding of this complex process.

Sphingosine-1-phosphate Phosphatase 1 Regulates Keratinocyte Differentiation and Epidermal Homeostasis

“…Sphingolipids are recognized for their importance in skin biology as both structural and signaling molecules (27)(28)(29)(30). Recently, S1P has been shown to have signaling properties that regulate keratinocyte cell function (31)(32)(33)(34)(35)(36).…”

Shedding and uptake of gangliosides and glycosylphosphatidylinositol-anchored proteins

“…It has been suggested that its association with the cell membrane proceeds through the interaction with membrane gangliosides [118,119]. Prosaposin can also be found in many biological fluids such as seminal plasma, human milk, and cerebrospinal fluid (reviewed in [120]). Prosaposin is abundant in the brain where it is localized exclusively in certain neurons [121].…”

“…Both prosaposin and shed gangliosides were reported to be present in milk and cerebrospinal fluid [120,149,150]. Gangliosides are being actively shed from the membranes [15], and this process appears to be regulated, indicating that it includes specific protein activity.…”

A Stretch of 17 Amino Acids in the Prosaposin C Terminus Is Critical for Its Binding to Sortilin and Targeting to Lysosomes

“…SAPs include five activator proteins, the G M2 activator protein (G M2 AP), and saposins A, B, C, and D (Schuette et al 2001). SAPs act as biological detergents by facilitating the interaction of glycosphingolipid substrates with their respective enzymes for degradation, since glycosphingolipids are unable to interact directly with hydrolytic enzymes in a hydrosoluble milieu (O'Brien and Figure 4 Lysosomal transport of prosaposin truncation/mutation constructs.…”

“…Error bars indicate 6 SE, and double asterisks represent p,0.01, compared with PSAP-WT. Kishimoto 1991;Furst and Sandhoff 1992;Mahuran 1998;Schuette et al 2001). Unlike the G M2 AP, saposins A-D derive from a common precursor protein, prosaposin (Hiraiwa et al 1997).…”