Lyso-glycosphingolipids: presence and consequences

Abstract

Lyso-glycosphingolipids are generated in excess in glycosphingolipid storage disorders. In the course of these pathologies glycosylated sphingolipid species accumulate within lysosomes due to flaws in the respective lipid degrading machinery. Deacylation of accumulating glycosphingolipids drives the formation of lyso-glycosphingolipids. In lysosomal storage diseases such as Gaucher Disease, Fabry Disease, Krabbe disease, GM1 -and GM2 gangliosidosis, Niemann Pick type C and Metachromatic leukodystrophy massive intra-lysosomal glycosphingolipid accumulation occurs. The lysosomal enzyme acid ceramidase generates the deacylated lyso-glycosphingolipid species. This review discusses how the various lyso-glycosphingolipids are synthesized, how they may contribute to abnormal immunity in glycosphingolipid storing lysosomal diseases and what therapeutic opportunities exist.

Keywords: acid ceramidase; glycosphingolipid; immune response; lysosomal storage disease.

Figure 1. Metabolism of glycosphingolipids

(A) Schematic representation of the de novo synthesis of sphingolipids. SPT: serine palmitoyltransferase. KDR: ketoreductase. CERS: ceramide synthase. DES: desaturase. The acylchain is depicted in blue and can range from C14-C26 depending on the CERS enzyme involved in acyl chain condensation (six CERS members exist). Depending on the acyl-CoA moiety used by SPT, i.e. myristoyl-CoA, palmitoyl-CoA or stearyl-CoA different sphingoid bases can be produced (C16:1, C18:1 or C20:1). (B) Generation of ceramide derived species including glycosphingolipids. CK: ceramide kinase. GCS: glucosylceramide synthase. SMS: sphingomyelin synthase. CGT: UDP-galactose ceramide galactosyl transferase. CGS: cerebroside sulfotransferase. CDase: ceramidase. SK: sphingosine kinase. S1PL: S1P lyase. LCS: lactosylceramide synthase. Cer1P: ceramide-1-phosphate. GlcCer: glucosylceramide. LacCer: lactosylceramide. GalCer: galactosylceramide. SO: sphingosine. S1P: sphingosine-1-phosphate. PE: phosphatidylethanolamine. Hexa: hexadecanal. (C) Lysosomal degradation of GSL with responsible gene products and diseases connected to defects. GLB1 (β-galactosidase), HEXA (β-hexosaminidase A), HEXB (β-hexosaminidase B), NEU3/4 (neuraminidase 3/4), GLA (α-galactosidase A), GBA (β-glucocerebrosidase), ASA (Arylsulfatase A), GALC (β-galactosylceramidase), ASAH1 (acid ceramidase).

Figure 2. Generation of lyso-glycosphingolipids

Schematic representation of (A). The generation of lyso-GSL by the action of acid ceramidase (AC). (B) From left to right. The lysosomal storage disorders, the gene defect, accumulating lysosomal GSL substrates and the deacylated lyso-GSL species. GBA, acid β-glucosidase. GALC, β-galactosylceramidase. GLA, α-galactosidase A. GLB1, β-galactosidase. HEX, β-hexosaminidase. ASA, Arylsulfatase A. GlcCer, glucosylceramide. GalCer, galactosylceramide. GB3, globotriaosylceramide. GM1, ganglioside GM1. GM2, ganglioside GM2. SO, sphingoid.

Figure 3. Simplified model of immune activation by (lyso)-GSL in LSD

1. Direct recognition of lyso-GSL by toll-like receptor 4 (TLR4). 2. CD1d-restricted lyso-GSL presentation and activation of type II iNKT cells. 3. iNKT cell-mediated activation of B cells and plasma cells. 4. Production of anti-(lyso)-GSL autoantibodies by plasma cells. 5. Continuous antibody production may result in genetic instability driving cancer cell formation. 6. Glucosylceramide (GC)-immune complexes (IC) interact with Fcγ-R inducing C5a (part of complement system), which by binding to C5aR1 triggers induction of more GlcCer (and connected GlcSph). APC, antigen presenting cell.

Figure 4. Summary of the actions of the various lyso-GSL species

Abbreviations: CNS, central nervous system; DC, dendritic cell; NKT, natural killer T; NO, nitric oxide; PBMC, peripheral blood mononuclear cell; PKC, protein kinase C.