title: De novo ceramide synthesis is required for N-linked glycosylation in plasma cells.
abstract: Plasma cells (PCs) are terminally differentiated B lymphocytes responsible for the synthesis and secretion of Igs. The differentiation of B cells into PCs involves a remarkable expansion of both lipid and protein components of the endoplasmic reticulum. Despite their importance in many signal transduction pathways, the role of ceramides, and of complex sphingolipids that are derived from ceramide, in PC differentiation has never been directly studied. To assess their putative role in PC differentiation, we blocked ceramide synthesis with fumonisin B1, a specific inhibitor of ceramide synthase. Under fumonisin B1 treatment, N-linked glycosylation was severely impaired in LPS-activated, but not in naive, B cells. We also show that ceramide synthesis is strongly induced by XBP-1 (X box-binding protein-1). In the absence of ceramide synthesis, ER expansion was dramatically diminished. Our results underscore ceramide biosynthesis as a key metabolic pathway in the process of PC differentiation and reveal a previously unknown functional link between sphingolipids and N-linked glycosylation in PCs.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, The Hebrew University, Jerusalem, Israel.
authors.forename: Meidan
authors.initials: M
authors.lastname: Goldfinger
authors.forename: Elad L
authors.initials: EL
authors.lastname: Laviad
authors.forename: Rivka
authors.initials: R
authors.lastname: Hadar
authors.forename: Miri
authors.initials: M
authors.lastname: Shmuel
authors.forename: Arie
authors.initials: A
authors.lastname: Dagan
authors.forename: Hyejung
authors.initials: H
authors.lastname: Park
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.forename: Israel
authors.initials: I
authors.lastname: Ringel
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.forename: Boaz
authors.initials: B
authors.lastname: Tirosh
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002518:Ceramides / Q000096:biosynthesis*; D004268:DNA-Binding Proteins; D037341:Fumonisins / Q000494:pharmacology; D006031:Glycosylation; D008070:Lipopolysaccharides / Q000494:pharmacology; D053858:Metabolic Networks and Pathways; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010950:Plasma Cells / Q000166:cytology / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
chemical_list: D002518:Ceramides; D004268:DNA-Binding Proteins; D037341:Fumonisins; D008070:Lipopolysaccharides; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C056933:fumonisin B1; D010088:Oxidoreductases; C108138:dihydroceramide desaturase