Nuclear sphingolipid metabolism

Abstract

Nuclear lipid metabolism is implicated in various processes, including transcription, splicing, and DNA repair. Sphingolipids play roles in numerous cellular functions, and an emerging body of literature has identified roles for these lipid mediators in distinct nuclear processes. Different sphingolipid species are localized in various subnuclear domains, including chromatin, the nuclear matrix, and the nuclear envelope, where sphingolipids exert specific regulatory and structural functions. Sphingomyelin, the most abundant nuclear sphingolipid, plays both structural and regulatory roles in chromatin assembly and dynamics in addition to being an integral component of the nuclear matrix. Sphingosine-1-phosphate modulates histone acetylation, sphingosine is a ligand for steroidogenic factor 1, and nuclear accumulation of ceramide has been implicated in apoptosis. Finally, nuclear membrane-associated ganglioside GM1 plays a pivotal role in Ca(2+) homeostasis. This review highlights research on the factors that control nuclear sphingolipid metabolism and summarizes the roles of these lipids in various nuclear processes.

Figure 1

The sphingolipid metabolic pathway. De novo biosynthesis begins with the condensation of serine and palmitoyl-CoA and various fatty acyl-CoAs. Ceramide can be generated through (a) de novo biosynthesis, (b) degradation of sphingomyelin (SM) or glucosyl-ceramides and galactosyl-ceramides, or (c) acylation of sphingosine (SPH). Ceramide can be phosphorylated into ceramide-1-phosphate (C1P) or hydrolyzed to form SPH, which is phosphorylated into sphingosine-1-phosphate (S1P). S1P can be either dephosphorylated to form SPH or irreversibly cleaved into phosphoethanolamine and hexadecenal. SPT denotes serine palmitoyltransferase.

Figure 2

Nuclear sphingomyelin (SM) metabolism. SM synthase catalyzes the formation of SM from ceramide and phosphatidylcholine (PC). SM can be degraded by sphingomyelinase (SMase), which generates phosphorylcholine (PPC) as a by-product, or by reverse SM synthase, which catalyzes the transfer of the PPC group in SM to diacylglycerol (DAG). Ceramide formed by SM hydrolysis can be phosphorylated into ceramide-1-phosphate or hydrolyzed into sphingosine, which can then be converted into its phosphorylated form, sphingosine-1-phosphate.

Figure 3

The localization of different sphingolipid species in subnuclear domains. The outer membrane is continuous with the endoplasmic reticulum, whereas the inner membrane is associated with the nuclear lamina. The nuclear pore allows passive flow of small molecules between the cytosol and the nucleoplasm. Abbreviations: S1P, sphingosine-1-phosphate; SM, sphingomyelin.

Figure 4

Ganglioside structure and biosynthetic pathway. Lactosyl-ceramide, formed by the addition of two carbohydrate moieties (glucose and galactose) to the terminal OH group of ceramide, is the precursor of gangliosides. GM1 has one terminal N-acetylneuraminic acid (sialic acid) group. GD1a, which has two terminal sialic acid groups, is converted into GM1 by neuraminidase.

Figure 5

Model for the role of sphingosine (SPH) in controlling the transactivation potential of steroidogenic factor 1 (SF-1). Under basal conditions, SPH is bound to SF-1 and corepressory proteins. Adrenocorticotropin hormone (ACTH) signaling activates protein kinase A (PKA), which promotes the release of SPH from the receptor’s ligand-binding pocket. Concomitantly, activation of the ACTH/cAMP pathway increases nuclear diacylglycerol kinase (DGK) activity, leading to increased phosphatidic acid (PA) biosynthesis. PA binding to SF-1 activates the receptor, thereby facilitating the recruitment of coactivator proteins and enabling interaction with the promoters of target genes. Abbreviations: GCN5, general control of amino acid synthesis protein 5; HDAC, histone deacetylase; PSF, polypyrimidine tract–binding protein–associated splicing factor; Sin3A, Sin3 homolog A; SMRT, silencing mediator for retinoid of thyroid hormone receptors; SRC1, steroid receptor coactivator 1.