The immunological functions of saposins

Abstract

Saposins or sphingolipid activator proteins (SAPs) are small, nonenzymatic glycoproteins that are ubiquitously present in lysosomes. SAPs comprise the five molecules saposins A-D and the GM2 activator protein. Saposins are essential for sphingolipid degradation and membrane digestion. On the one hand, they bind the respective hydrolases required to catabolize sphingolipid molecules; on the other hand, saposins can interact with intralysosomal membrane structures to render lipids accessible to their degrading enzymes. Thus, saposins bridge the physicochemical gap between lipid substrate and hydrophilic hydrolases. Accordingly, defects in saposin function can lead to lysosomal lipid accumulation. In addition to their specific functions in sphingolipid metabolism, saposins have membrane-perturbing properties. At the low pH of lysosomes, saposins get protonated and exhibit a high binding affinity for anionic phospholipids. Based on their universal principle to interact with membrane bilayers, we present the immunological functions of saposins with regard to lipid antigen presentation to CD1-restricted T cells, processing of apoptotic bodies for antigen delivery and cross-priming, as well as their potential antimicrobial impact.

Figure 2.1

Pathways of GSL degradation. The graph depicts the degradative pathways of various GSL species, including the globo-, isoglobo-, ganglio-, and (neo)lacto-series. The names, formula, and structural icons of the respective GSLs are shown in the boxes. The ovals contain the enzymes (depicted in blue) and the saposins (shown in red) that are involved in the corresponding lipid degradation step. The associated lysosomal storage disease due to enzyme or saposin deficiency or both is indicated in green.

Figure 2.2

Immunological functions of saposins. The central circle demonstrates the universal mechanism of saposin action on lipid bilayers. Accordingly, saposin molecules insert into lysosomal membranes to induce bilayer disintegration and lipid extraction. Further, the graph represents the three immunological consequences of this mechanism. (1) Lipid antigen presentation: In lysosomes of APCs, saposins interact with intralysosomal vesicles (ILVs) that contain lipid antigens. Subsequently, SAPs facilitate the loading of CD1 molecules with lipid antigens to activate CD1-restricted lipid-reactive T cells. (2) Processing of apoptotic bodies / cross-presentation: Apoptotic bodies derived from tumor or infected cells are engulfed by phagocytes such as DCs or macrophages. Protein antigens contained in apoptotic vesicles are liberated in lysosomes upon membrane disintegration induced by saposins. This leads to antigen delivery from apoptotic bodies for subsequent cross-presentation of antigens to MHC-I-restricted CD8⁺ T cells. (3) Antibiotic function: Pathogens like intracellular bacteria are phagocytosed by macrophages or DCs. At the acidic pH of lysosomes, saposins unfold their antimicrobial effects through direct attack on the membranes of pathogens.