Molecular mechanisms and regulation of ceramide transport.
De novo biosynthesis of sphingolipids begins in the endoplasmic reticulum (ER) and continues in the Golgi apparatus and plasma membrane. A crucial step in sphingolipid biosynthesis is the transport of ceramide by vesicular and non-vesicular mechanisms from its site of synthesis in the ER to the Golgi apparatus. The recent discovery of the ceramide transport protein CERT has revealed a novel pathway for the delivery of ceramide to the Golgi apparatus for sphingomyelin (SM) synthesis. In addition to a ceramide-binding START domain, CERT has FFAT (referring to two phenylalanines [FF] in an acidic tract) and pleckstrin homology (PH) domains that recognize the ER integral membrane protein VAMP-associated protein (VAP) and Golgi-associated PtdIns 4-phosphate, respectively. Mechanisms for vectorial transport involving dual-organellar targeting and sites of deposition of ceramide in the Golgi apparatus are proposed. Similar Golgi-ER targeting motifs are also present in the oxysterol-binding protein (OSBP), which regulates ceramide transport and SM synthesis in an oxysterol-dependent manner. Consequently, this emerges as a potential mechanism for integration of sphingolipid and cholesterol metabolism. The identification of organellar targeting motifs in other related lipid-binding/transport proteins indicate that concepts learned from the study of ceramide transport can be applied to other lipid transport processes.
Perry
Ryan J
RJ
Atlantic Research Centre, Dalhousie University, 5849 University Avenue, Halifax, N.S., Canada B3H 4H7.
Ridgway
Neale D
ND
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002518:Ceramides / Q000096:biosynthesis / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005963:Glucosylceramides / Q000096:biosynthesis; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013109:Sphingomyelins / Q000096:biosynthesis
D002518:Ceramides; D005963:Glucosylceramides; D013109:Sphingomyelins; C119090:CERT1 protein, human; D017346:Protein Serine-Threonine Kinases