Structure, functions and regulation of CERT, a lipid-transfer protein for the delivery of ceramide at the ER-Golgi membrane contact sites.

The inter-organelle transport of lipids must be regulated to ensure appropriate lipid composition of each organelle. In mammalian cells, ceramide synthesised in the endoplasmic reticulum (ER) is transported to the trans-Golgi regions, where ceramide is converted to sphingomyelin (SM) with the concomitant production of diacylglycerol. Ceramide transport protein (CERT) transports ceramide from the ER to the trans-Golgi regions at the ER-Golgi membrane contact sites (MCS). The function of CERT is down-regulated by multisite phosphorylation of a serine-repeat motif (SRM) and up-regulated by phosphorylation of serine 315 in CERT. Multisite phosphorylation of the SRM is primed by protein kinase D, which is activated by diacylglycerol. The function of CERT is regulated by a phosphorylation-dependent feedback mechanism in response to cellular requirements of SM. CERT-dependent ceramide transport is also affected by the pool of phosphatidylinositol (PtdIns)-4-phosphate (PtdIns(4)P) in the trans-Golgi regions, while the PtdIns(4)P pool is regulated by PtdIns-4-kinases and oxysterol-binding protein. The ER-Golgi MCS may serve as inter-organelle communication zones, in which many factors work in concert to serve as an extensive rheostat of SM, diacylglycerol, cholesterol and PtdIns(4)P.