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Papers In Press, published online ahead of print October 1, 2009
J. Lipid Res., doi:10.1194/jlr.M900097-JLR200

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Journal of Lipid Research, Vol. 50, 2103-2110, October 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Regulation of primary cilia formation by ceramide^[S]

Guanghu Wang, Kannan Krishnamurthy and Erhard Bieberich

Program in Developmental Neurobiology, Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia, 1120 15th Street Room CB-2803, Augusta, GA 30912

¹ To whom correspondence should be addressed. e-mail: ebieberich{at}mcg.edu

The primary cilium is an important sensory organelle, the regulation of which is not fully understood. We found that in polarized Madin-Darby Canine Kidney cells, the sphingolipid ceramide is specifically distributed to a cis-Golgi compartment at the base of the primary cilium. This compartment immunostained for the centrosome marker -tubulin, the Rho type GTPase cell division cycle 42 (Cdc42), and atypical protein kinase C/ (aPKC), a kinase activated by ceramide and associated with a polarity protein complex consisting of partitioning defective (Par)6 and Cdc42. Inhibition of ceramide biosynthesis with Fumonisin B1 prevented codistribution of aPKC and Cdc42 in the centrosomal/pericentriolar compartment and severely impaired ciliogenesis. Cilium formation and codistribution of aPKC and Cdc42 were restored by incubation with N-acetyl or N-palmitoyl sphingosine (C2 or C16 ceramide), or the ceramide analog N-oleoyl serinol (S18). Cilium formation was also restored by the glycogen synthase kinase-3β (GSK-3β) inhibitor indirubin-3-monoxime, suggesting that regulation of ciliogenesis depends on the inhibition of GSK-3β by ceramide-activated aPKC. Consistently, inhibition of aPKC with a pseudosubstrate inhibitor prevented restoration of ciliogenesis by C2 ceramide or S18. Our data show for the first time that ceramide is required for primary cilium formation.—Wang, G., K. Krishnamurthy, and E. Bieberich. Regulation of primary cilia formation by ceramide.

Supplementary key words sphingolipids • cell polarity • primary cilium • Golgi • centrosome

Abbreviations: aPKC, atypical protein kinase C (PKC, /); Cdc42, cell division cycle 42; ER, endoplasmic reticulum; FB1, fumonisin B1; HPTLC, high-performance thin-layer chromatography; GM130, Golgi matrix 130; GSK-3β, glycogen synthase kinase-3β; MDCK, Madin Darby Canine Kidney; Par, partitioning defective; PCM, pericentriolar material; PZI, pseudosubstrate inhibitor of PKC (aPKC); S18, N-oleoyl serinol; SPT, serine palmitoyltransferase; WGA, wheat germ agglutinin

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