Thursday 4 December 2003
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer.
Ceramide can be released from the cell membrane by enzymes and then act as a signaling molecule. The most well-known functions of ceramides as cellular signals include regulating the differentiation, proliferation, programmed cell death, and apoptosis of cells.
The sphingoplipid ceramide is responsible for a diverse range of biochemical and cellular responses including a putative role in modulating cell cycle progression.
The conversion of sphingomyelin into ceramide can play a membrane structural (physical) role, with consequences for membrane microdomain function, membrane vesiculation, fusion/fission and vesicular trafficking. These processes contribute to cellular signalling.
At the Golgi, ceramide takes part in a metabolic flux towards sphingomyelin, diacylglycerol and glycosphingolipids, which drives lipid raft formation and vesicular transport towards the plasma membrane.
At the cell surface, receptor clustering in lipid rafts and the formation of endosomes can be facilitated by transient ceramide formation. Also, signalling towards mitochondria may involve glycosphingolipid-containing vesicles.
Ceramide may affect the permeability of the mitochondrial outer membrane and the release of cytochrome c. In the effector phase of apoptosis, the breakdown of plasma membrane sphingomyelin to ceramide is a consequence of lipid scrambling, and may regulate apoptotic body formation. Thus ceramide formation serves many different functions at distinct locations in the cell.
The ceramide signaling pathway
The sphingolipid, ceramide, a second messenger activated through the tumor necrosis factor (TNF) receptor, is a mediator of pro-apoptotic events.
It is produced by two distinct, membrane-associated neutral (N-SMase) and an endosomal acidic (A-SMase), sphingomyelinases which cleave sphingomyelin.
These SMases are activated through binding to the 55 kDa TNF receptor (TNF-R55) via different domains. Downstream signaling by ceramide is dependent upon which SMase produces it.
Ceramide can activate phosphatases such as protein phosphatase I (PP1) and protein phosphatase 2A (PP2A). These phosphatases can inactivate survival signaling molecules such as classical and novel PKC isoforms and Akt/PKB. They can also activate pro-apoptotic factors such as BAD and BAX.
Ceramide signals activation of the Ras (KSR)/ceramide-activated protein kinase (CAPK), Ras, c-Raf-1, MEK1, ERK pathway. This pathway is pro-growth but it becomes pro-apoptotic in the presence of dephosphorylated BAD.
Direct interaction of ceramide with pre-pro cathepsin D results in autocatalytic proteolysis and formation of cathepsin D. Cathepsin D has been linked to mitochondrial apoptosis through cleavage of BiD.
Ceramide promotes activation of PKCzeta by phosphorylation, which in turn promotes NFkappaB mediated cell survival. However, when PAR-4 (prostate apoptosis response-4) is also present it promotes apoptosis. Ceramide-1-phosphate (Sph-1-P) blocks apoptosis by inhibiting acidic sphingomyleinase.
Ceramide and lung inflammation
Ceramide is produced from membrane sphingomyelin by the enzyme acid sphingomyelinase, which is activated by several causes of lung injury, including platelet-activating factor (PAF) and tumor necrosis factor-alpha (TNF-alpha).
Ceramide generates sphingosine-1-phosphate (S1P), which in turn activates the transcription factors (NF-kappaB) and AP-1.
Secreted S1P can activate G-protein-coupled receptors (GPCRs), including endothelial differentiation gene (EDG) receptors (EDGRs).
Ceramide may also induce endothelial cells to produce inflammatory mediators, such as PAF and TNF-alpha, thus perpetuating injury. Ceramide may also induce apoptosis of endothelial cells and type I pneumocytes, and damage type 2 pneumocytes, thus leading to pulmonary edema.
van Blitterswijk WJ, van der Luit AH, Veldman RJ, Verheij M, Borst J. Ceramide: second messenger or modulator of membrane structure and dynamics? Biochem J. 2003 Jan 15;369(Pt 2):199-211. PMID: 12408751
Basu, S. et al. (1998) BAD enables ceramide to signal apoptosis via Ras and Raf-1. J. Biol. Chem. 273, 30419-30426.
Ruvolo, P. P. (2003) Intracellular signal transduction pathways activated by ceramide and its metabolites. Pharmacol. Res. 47, 383-392.
Wang, G. et. al. (2005) Direct binding to ceramide activates protein kinase Czeta before the formation of a pro-apoptotic complex with PAR-4 in differentiating stem cells. J. Biol. Chem. 280, 26415-26424.
Wiegmann, K. et. al. (1994) Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell. 78, 1005-1015