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Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER

¹ Membrane Enzymology, Bijvoet Center and Institute of Biomembranes, and ² Biochemistry and Cell Biology, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, Netherlands
³ The Cell Microscopy Center, Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands
⁴ Medical Biochemistry, Institute of Biomedicine, University of Helsinki, Helsinki 00014, Finland

Correspondence to Philipp Ternes: pternes{at}uni-goettingen.de; or Joost C.M. Holthuis: j.c.holthuis{at}uu.nl

Ceramides are central intermediates of sphingolipid metabolism with critical functions in cell organization and survival. They are synthesized on the cytosolic surface of the endoplasmic reticulum (ER) and transported by ceramide transfer protein to the Golgi for conversion to sphingomyelin (SM) by SM synthase SMS1. In this study, we report the identification of an SMS1-related (SMSr) enzyme, which catalyses the synthesis of the SM analogue ceramide phosphoethanolamine (CPE) in the ER lumen. Strikingly, SMSr produces only trace amounts of CPE, i.e., 300-fold less than SMS1-derived SM. Nevertheless, blocking its catalytic activity causes a substantial rise in ER ceramide levels and a structural collapse of the early secretory pathway. We find that the latter phenotype is not caused by depletion of CPE but rather a consequence of ceramide accumulation in the ER. Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER.

P. Ternes' present address is Albrecht-von-Haller Institut für Plantzenwissenschaften, 37077 Göttingen, Germany

Abbreviations used in this paper: CERT, ceramide transfer protein; CPE, ceramide phosphoethanolamine; CPES, CPE synthase; ds GFP, dsRNA-targeting GFP; ds SMSr, dsRNA-targeting SMSr; dSMSr, Drosophila SMSr; dsRNA, double-stranded RNA; g_av, average g; GlcCer, glucosylceramide; HB, homogenization buffer; hSMSr, human SMSr; LA, lamin A; LCB, long-chain base; MS, mass spectrometry; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PEMT, PE N-methyltransferase; PM, plasma membrane; PNS, postnuclear supernatant; SAM, sterile motif; si hSMSr, siRNA-targeting hSMSr; si LA, siRNA-targeting LA; SM, sphingomyelin; SMS, SM synthase; SMSr, SMS related; tER, transitional ER.

© 2009 Vacaru et al.
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This article has been cited by other articles:

• Ternes, P., Brouwers, J. F. H. M., van den Dikkenberg, J., Holthuis, J. C. M. (2009). Sphingomyelin synthase SMS2 displays dual activity as ceramide phosphoethanolamine synthase. J. Lipid Res. 50: 2270-2277 [Abstract] [Full Text]  

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