Some (e.g. Gulbins and Kolesnic, Oncogene 22:7070 (2003)) argue that sphingomyelin can be cleaved to ceramides in the plasma membrane, forming lipid rafts. This is outlined as a control pathway, for example in apoptosis by clustering death receptors (see Summers, Prog. Lipid Res. 45: 42-72 (2006)). However, the topology is all wrong. The pathway for breakdown of these lipids require them to first enter the lysozome. Since sphingolipids face the cell exterior, there is no means of enzymatic attack on the phosphate ester since that is in the exterior water phase. Seems simple, but it makes little sense. The type of signaling suggested for sphingolipids seems unconcerned with cellular location.
Hey Raymond,
My lab works more in sphingosine and S1P than sphingomyelin, but I can see the topical argument you present. I think however that there are 2 assumptions that may be leading you down the wrong path.
The first is that sphingolipids are exclusively on the exterior of the cell, whereas the ASM is acting on the interior. In reality sphingolipids are decorating both sides of the bilayer, as evidenced by the association of Sphingosine Kinase 1 with the plasma membrane during endocytic vesicle formation and the subsequent production of S1P from cytosolic facing sphingosine. In this case however that does not answer your question, as SMase works on SM. It has been shown however through exocytosis ASMase is secreted into the extracellular space where it can then act on extracellular facing SM producing ceramide.
The second, and perhaps more important issue is that breakdown of sphingolipids occurs in the lysosome. This is not true , however. There is ample literature showing nSMase localization in the ER, and literature showing ceramidase activity at the plasma membrane.
A good way to approach it would be to assume that the degradation of endocytosed membranes occurs in the lysosome, with aSMase responsible for the degradation of SM, and all SLs being reduced to sphingosine inside the lysosome. However there are clustered localizations of sphingolipid catabolic enzymes at the site of sphingolipid synthesis (the ER), and signaling can occur at the plasma membrane through ceramidase, aSMase, and Sphingosine Kinase 1. I lump SphK1 as a catabolic enzyme for this conversation as the conversion of Sphingosine to S1P is required for the subsequent irreversible degradation of all sphingolipids by S1P lyase- which evidence strongly suggests occurs exclusively in the ER.
I apologize if I made things more confusing, and if there are typos as I tend to get autocorrected by this website.
There is a good review by Yusuf Hannun in Cell Signaling that may explain the aSMase issue more coherently than I have. (PMID: 19385042)
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