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Review
. 2008 Jun;49(6):1176-86.
doi: 10.1194/jlr.R800009-JLR200. Epub 2008 Mar 9.

Nuclear sphingolipids: metabolism and signaling

Robert W Ledeen  1 , Gusheng Wu
Affiliations
Review

Nuclear sphingolipids: metabolism and signaling

Robert W Ledeen et al. J Lipid Res. 2008 Jun.

Abstract

Sphingolipids are most prominently expressed in the plasma membrane, but recent studies have pointed to important signaling and regulatory roles in the nucleus. The most abundant nuclear sphingolipid is sphingomyelin (SM), which occurs in the nuclear envelope (NE) as well as intranuclear sites. The major metabolic product of SM is ceramide, which is generated by nuclear sphingomyelinase and triggers apoptosis and other metabolic changes. Ceramide is further hydrolyzed to free fatty acid and sphingosine, the latter undergoing conversion to sphingosine phosphate by action of a specific nuclear kinase. Gangliosides are another type of sphingolipid found in the nucleus, members of the a-series of gangliotetraose gangliosides (GM1, GD1a) occurring in the NE and endonuclear compartments. GM1 in the inner membrane of the NE is tightly associated with a Na(+)/Ca(2+) exchanger whose activity it potentiates, thereby contributing to regulation of Ca(2+) homeostasis in the nucleus. This was shown to exert a cytoprotective role as absence or inactivation of this nuclear complex rendered cells vulnerable to apoptosis. This was demonstrated in the greatly enhanced kainite-induced seizure activity in knockout mice lacking gangliotetraose gangliosides. The pathology included apoptotic destruction of neurons in the CA3 region of the hippocampus. Ca(2+) homeostasis was restored in these animals with LIGA-20, a membrane-permeant derivative of GM1 that entered the NE and activated the nuclear Na(+)/Ca(2+) exchanger. Some evidence suggests the presence of uncharged glycosphingolipids in the nucleus.

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Figures

Fig. 1.
Fig. 1.
Representation of nuclear structure with endonuclear domains, as presently conceived. The outer nuclear membrane is continuous with the endoplasmic reticulum (ER), while the inner nuclear membrane is closely associated with the nuclear lamina and has a unique lipid composition. These two membranes are joined at the nuclear pore complexes that are distributed over the nuclear surface and permit passive flow of small molecules between cytoplasm and nucleoplasm. The lumenal space between the two membranes of the nuclear envelope (NE) is a storage site for Ca2+, continuous with the ER lumen. In addition to the NE, lipids have been shown to occur in intranuclear compartments such as nucleolus, chromatin, and heterochromatin. Reproduced from Fig. 1 of ref. with permission.
Fig. 2.
Fig. 2.
Sphingomyelin (SM), the major sphingolipid of nuclei, and its metabolic pathways in mammalian nuclei. All indicated reactions have been shown to occur in the nucleus, with the exception of pathways with dashed arrows, viz., ceramide (CER) kinase. In addition, possible catabolism of sphingosine-1-phosphate (S-1-P) via S-1-P phosphatase and/or S-1-P lyase, known to occur in other subcellular compartments, has not yet been detected in the nucleus. A single fatty acid component (C16) of CER is shown, but other chain lengths are possible. DAG, diacylglycerol; PC, phosphatidylcholine; SMase, sphingomyelinase.
Fig. 3.
Fig. 3.
Cytochemical evidence for copresence of GM1 and Na+/Ca2+ exchanger (NCX) in the NE of cultured neuronal cells. GM1 was detected with Ctx B–horseradish peroxidase, and NCX with anti-NCX antibody plus horseradish peroxidase–linked second antibody. GM1 expression was observed in the NE of differentiated neuro2A cells (A), rat cerebellar granular neurons (B), and rat superior cervical ganglion neurons (C). GM1 expression in the NE of differentiated (D) and undifferentiated (E) NG108-15 cells yielded scant GM1 in the NE of the latter and elevated GM1 in the NE of former. NCX expression was observed in the NE of differentiated NG108-15 cells (F). Arrowheads indicate staining of NE and arrows represent staining of plasma membrane. The bar represents 20 micrometers.
Fig. 4.
Fig. 4.
Proposed topology of GM1 and Na+/Ca2+ exchanger (NCX) in the nuclear envelope (NE; A) and plasma membrane (PM; B). In both cases the large loop between transmembrane units 5 and 6 is located on the low Ca2+ side (i.e., cytoplasm for PM and nucleoplasm for NE). This accords with the demonstrated location of both GM1 and NCX in the inner membrane of the NE and occurrence of the large NCX loop in proximity to the GM1 oligosaccharide chain. The authors propose that the high-affinity association of GM1 with NCX arises from the negative charge of N-acetylneuraminic acid in GM1 interacting with the alternative splice region (ASR) of the NCX loop, some of whose isoforms are enriched in positively charged amino acids. Such association is not possible for the PM, because the NCX loop and GM1 oligosaccharide occur on opposite sides of the membrane. INM, inner nuclear membrane; ONM, outer nuclear membrane.
Fig. 5.
Fig. 5.
Glycosphingolipid structures. GM1, revealed as one of the major nuclear gangliosides in the authors' studies, has R = H. GD1a, the other major ganglioside of neural cells (not shown), has R = NeuAc. LIGA-20 is a semisynthetic derivative of GM1, more membrane permeant than the latter, in which the long-chain fatty acid of CER is replaced by dichloroacetyl. Globotriaosylceramide (Gb3CER) was suggested to occur in the NE (–99), but this requires confirmation.
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