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

Abstract

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.

Mammalian ORMDL Proteins Mediate the Feedback Response in Ceramide Biosynthesis

“…1, A-C). However, it is clear that depletion of SMSr elevates steady-state levels of ceramide (12). We conclude that the major site of SMSr regulation of ceramide is not at the level of biosynthesis, but rather by regulating one or more of the upstream metabolic processes that determine ceramide levels.…”

“…However, the mechanism by which the ORMDL proteins regulate ceramide levels and whether they are responsive to changes in cellular ceramide content have not been established. Mammalian cells also express a member of the sphingomyelin synthase family, SMSr, which has been implicated as a ceramide sensor in ceramide homeostasis (12). SMSr generates phosphoethanolamine-ceramide rather than sphingomyelin, is a low efficiency enzyme and, unlike the conventional sphingomyelin synthases, is localized in the endoplasmic reticulum rather than in the Golgi apparatus.…”

Tales and Mysteries of the Enigmatic Sphingomyelin Synthase Family

“…58 Indeed, we recently demonstrated that Drosophila and human SMSr proteins catalyze EPC biosynthesis and, contrary to SMS1 and SMS2, localize to the ER. 69 SMSr thus qualifies as the ER-resident CPE synthase originally described by Malgat et al 41,42 Remarkably, we have recently found that SMSr produces only trace amounts of CPE and that bulk production of CPE in Drosophila S2 cells requires a different enzyme. This second, insect-specific CPE synthase uses CDP-ethanolamine instead of PE as headgroup donor, 69 analogous to the ethanolaminephosphotransferases of the Kennedy pathway.…”

“…69 SMSr thus qualifies as the ER-resident CPE synthase originally described by Malgat et al 41,42 Remarkably, we have recently found that SMSr produces only trace amounts of CPE and that bulk production of CPE in Drosophila S2 cells requires a different enzyme. This second, insect-specific CPE synthase uses CDP-ethanolamine instead of PE as headgroup donor, 69 analogous to the ethanolaminephosphotransferases of the Kennedy pathway. 70 This implies that, contrary to SM synthesis in mammals, bulk production of CPE in insects occurs in the cytosolic leaflet of the membrane.…”

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

“…This ER-localized protein, SMSr is homologous to SM synthase but lacks SM synthase activity, having instead a weak ability to generate ceramide-phosphoethanolamine (CPE). Surprisingly, knockdown of SMSr causes a dramatic increase in ceramide levels that cannot be explained by a block in CPE production (Vacaru et al 2009). Rather, SMSr may act as a sensor that detects ER ceramides and down-regulates ceramide production.…”