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Link to original content: https://pubmed.ncbi.nlm.nih.gov/17161984
A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death - PubMed Skip to main page content
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Review
. 2006 Dec;1758(12):2027-36.
doi: 10.1016/j.bbamem.2006.10.018. Epub 2006 Nov 1.

A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death

Tarek A Taha  1 , Thomas D Mullen, Lina M Obeid
Affiliations
Review

A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death

Tarek A Taha et al. Biochim Biophys Acta. 2006 Dec.

Abstract

Programmed cell death is an important physiological response to many forms of cellular stress. The signaling cascades that result in programmed cell death are as elaborate as those that promote cell survival, and it is clear that coordination of both protein- and lipid-mediated signals is crucial for proper cell execution. Sphingolipids are a large class of lipids whose diverse members share the common feature of a long-chain sphingoid base, e.g., sphingosine. Many sphingolipids have been shown to play essential roles in both death signaling and survival. Ceramide, an N-acylsphingosine, has been implicated in cell death following a myriad of cellular stresses. Sphingosine itself can induce cell death but via pathways both similar and dissimilar to those of ceramide. Sphingosine-1-phosphate, on the other hand, is an anti-apoptotic molecule that mediates a host of cellular effects antagonistic to those of its pro-apoptotic sphingolipid siblings. Extraordinarily, these lipid mediators are metabolically juxtaposed, suggesting that the regulation of their metabolism is of the utmost importance in determining cell fate. In this review, we briefly examine the role of ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death and highlight the potential roles that these lipids play in the pathway to apoptosis.

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Figures

Figure 1
Figure 1. Multiple pathways of cellular stress lead to MMP and apoptosis
Genotoxic stress activates p53 and “BH-3 only” proteins such as Noxa and Puma that promote MMP and the release of death factors from the mitochondrion. Cathepsins are released during lysosomal stress and result in the cleavage of Bid, which translocates to the mitochondrion to promote MMP. ER stress can be manifested by dysregulation of calcium homeostasis and subsequent accumulation of calcium in the mitochondria, leading to MMP. Finally, death receptor activation can lead to a multifaceted pathway that may involve lysosomal disruption, caspase 8-mediated Bid cleavage, mitochondrial disruption, and caspase activation.
Figure 2
Figure 2. Ceramide is a central mediator of many apoptotic pathways
Following genotoxic stress, ceramide accumulates, but it is still unclear whether the increase is dependent or independent of p53. Signaling through the lysosomes involves increases in ceramide via aSMase. Ceramide can directly activate the lysosomal protease cathepsin D which can subsequently cleave and activate Bid. Another direct target of ceramide is protein phosphatase 2A, which is known to negatively regulate the prosurvival kinase Akt/PKB. Both PP2A and Akt/PKB regulate the Bax/Bcl-2 rheostat; if the PP2A prevails, as is the case in ceramide signaling, Bax prevails over Bcl-2 and the mitochondrion is permeabilized. Death receptor activation can lead to ceramide formation via nSMase and caspase 8-mediated cleavage of Bid; lysosomes may also be activated downstream of death receptors, with both signals converging on MMP. Additionally, generation of ceramide from sphingomyelin hydrolysis in mitochondria results in Bax translocation and MMP.
Figure 3
Figure 3. Sphingosine and S1P in apoptosis
(A) Sphingosine mediates cell death through the inhibition of the prosurvival factors PKC and Akt/PKB and induces death via SDK1, which leads to Bax activation through inhibition of 14-3-3 proteins. (B) S1P inhibits apoptosis by activating prosurvival factors such as Akt/PKB, NF-κ B, ERK, and NO. Ceramide-induced death may also be inhibited by S1P through the inactivation JNK or other factors that promote PCD.
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