title: 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.
authors.affiliation: Membrane Enzymology, Bijvoet Center and Institute of Biomembranes, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, Netherlands.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Vacaru
authors.forename: Fikadu G
authors.initials: FG
authors.lastname: Tafesse
authors.forename: Philipp
authors.initials: P
authors.lastname: Ternes
authors.forename: Vangelis
authors.initials: V
authors.lastname: Kondylis
authors.forename: Martin
authors.initials: M
authors.lastname: Hermansson
authors.forename: Jos F H M
authors.initials: JF
authors.lastname: Brouwers
authors.forename: Pentti
authors.initials: P
authors.lastname: Somerharju
authors.forename: Catherine
authors.initials: C
authors.lastname: Rabouille
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Holthuis
mesh_terms: D000818:Animals; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D006056:Golgi Apparatus / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D010802:Phylogeny; D034622:RNA Interference; D055571:Secretory Pathway / Q000502:physiology; D013109:Sphingomyelins / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000145:classification / Q000235:genetics / Q000378:metabolism*
chemical_list: D002518:Ceramides; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D013109:Sphingomyelins; C060281:ceramide phosphoethanolamine; C455440:SGMS1 protein, human; D017855:Transferases (Other Substituted Phosphate Groups)