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De Novo Ceramide Synthesis Is Required for N-Linked Glycosylation in Plasma Cells¹

Meidan Goldfinger^*, Elad L. Laviad, Rivka Hadar^*, Miri Shmuel^*, Arie Dagan, Hyejung Park, Alfred H. Merrill, Jr, Israel Ringel^*, Anthony H. Futerman and Boaz Tirosh^2,*

^* Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, The Hebrew University, Jerusalem, Israel; Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel; Department of Experimental Medicine and Cancer Research, Hebrew University Medical School, Jerusalem, Israel; and School of Biology and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The study was supported by research grants from the David R. Bloom Center for Pharmacy and Marie-Curie Reintegration Grant 046446 (to B.T.), and from the National Institutes of Health Grant GM076217 (to A.H.M. and A.H.F.). B.T. is affiliated with the David R. Bloom Center for Pharmacy at the Hebrew University (Jerusalem, Israel). A.H.F. is a Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute of Science.

² Address correspondence and reprint requests to Dr. Boaz Tirosh, Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel. E-mail address: boazt{at}ekmd.huji.ac.il

³ Abbreviations used in this paper: PC, plasma cell; ATF6, activating transcription factor 6; CCT, cytidine 5'-triphosphate:phosphocholine cytidylyltransferase ; CerS, ceramide synthases; CHX, cycloheximide; ER, endoplasmic reticulum; FB1, fumonisin B1; FSC, forward scatter; KO, knockout; LLO, lipid-linked oligosaccharides; NMR, nuclear magnetic resonance; PERK, PKR-like ER kinase; PtdCho, phosphatidylcholine; SM, sphingomyelin; Tm, tunicamycin; UPR, unfolded protein response; XBP-1, X box-binding protein-1; wt, wild type.

⁴ The online version of this article contains supplemental material.