The complex life of simple sphingolipids

Abstract

The extensive diversity of membrane lipids is rarely appreciated by cell and molecular biologists. Although most researchers are familiar with the three main classes of lipids in animal cell membranes, few realize the enormous combinatorial structural diversity that exists within each lipid class, a diversity that enables functional specialization of lipids. In this brief review, we focus on one class of membrane lipids, the sphingolipids, which until not long ago were thought by many to be little more than structural components of biological membranes. Recent studies have placed sphingolipids-including ceramide, sphingosine and sphingosine-1-phosphate-at the centre of a number of important biological processes, specifically in signal transduction pathways, in which their levels change in a highly regulated temporal and spatial manner. We outline exciting progress in the biochemistry and cell biology of sphingolipids and focus on their functional diversity. This should set the conceptual and experimental framework that will eventually lead to a fully integrated and comprehensive model of the functions of specific sphingolipids in regulating defined aspects of cell physiology.

Figure 1

The complexity of sphingolipid cell biology. The upper panel shows the structure of some sphingolipids. Note that, for simplicity, only one kind of sphingoid base (sphingosine, in blue) is shown to which only one kind of fatty acid (palmitic acid, in red) is N-acylated. Similarly, only one glycosphingolipid (GSL)—glucosylceramide (black)—is shown, but sequential addition of other carbohydrate residues results in >500 known GSL structures. The bottom panel shows metabolic pathways and the intracellular sites where some of these reactions occur. The topology is uncertain in some cases, particularly for the reactions that occur in the nucleus and mitochondria, and purportedly on the inner leaflet of the plasma membrane. Lipid building blocks are colour coded according to the structures shown above. Transport pathways of the lipids are not shown, but consist of vesicular and non-vesicular pathways.

Figure 2

The complexity of signalling with simple sphingolipids. In lipid signalling pathways, an input activates (either directly or indirectly) an enzyme that generates a lipid product, which results in an output signal as shown in the insert on the left of the figure. In the main panel of the figure, individual inputs (indicated by positive numbers when affecting a pathway that leads to ceramide and by negative numbers when affecting a pathway that leads away from ceramide) are shown in grey, the enzymes they affect are in blue, the lipids generated in black, and the outputs in red. Note the large diversity of inputs and the relationships between the different lipids generated as illustrated in the insert on the right, which shows what might happen if both the substrate and product are signalling lipids. This could give rise to diametrically opposed outputs, as indicated by the arrows connecting output 1 and 2. Note also that a number of other pathways, and other signalling sphingolipids, are not shown. Moreover, one input may regulate more than one enzyme, and a particular cell may receive more than one input at a time. Therefore, cell responses would be best described by the integration of responses to these (and other) pathways, which provides significant flexibility (but also complexity). The challenge in this field is to superimpose Fig 2 on Fig 1 so as to explain how the signalling events in Fig 2 are regulated, modulated and affected by the subcellular localizations at which they occur, and how this is regulated temporally. Lipids are shown using the same simplified structures as in Fig 1. Cer kin, ceramide kinase; Cer syn, ceramide synthase; Cer1PPase, ceramide-1-phosphate phosphatase; cPLA2, phospholipase A2; EDG receptors, endothelial differentiation gene receptors; SM, sphingomyelin; SM syn, SM synthase; SMase, sphingomyelinase (of which both neutral and acid act as signalling enzymes); S1PK, sphingosine kinase; S1PPase, sphingosine-1-phosphate phosphatase; PP1, protein phosphatase 1; PP2A, protein phosphatase 2A; cerase, ceramidase.