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J. Biol. Chem., Vol. 281, Issue 29, 19830-19839, July 21, 2006

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Ethanolaminephosphate Side Chain Added to Glycosylphosphatidylinositol (GPI) Anchor by Mcd4p Is Required for Ceramide Remodeling and Forward Transport of GPI Proteins from Endoplasmic Reticulum to Golgi^*

From the Department of Medicine/Biochemistry, University of Fribourg, CH-1700 Fribourg, Switzerlanda

Glycosylphosphatidylinositol (GPI) anchors of mammals as well as yeast contain ethanolaminephosphate side chains on the 1–4- and the 1–6-linked mannoses of the anchor core structure (protein-CO-NH-(CH₂)₂-PO₄-6Man1–2Man1–6Man1–4GlcNH₂-inositol-PO₄-lipid). In yeast, the ethanolaminephosphate on the 1–4-linked mannose is added during the biosynthesis of the GPI lipid by Mcd4p. MCD4 is essential because Gpi10p, the mannosyltransferase adding the subsequent 1–2-linked mannose, requires substrates with an ethanolaminephosphate on the 1–4-linked mannose. The Gpi10p ortholog of Trypanosoma brucei has no such requirement. Here we show that the overexpression of this ortholog rescues mcd4 cells. Phenotypic analysis of the rescued mcd4 cells leads to the conclusion that the ethanolaminephosphate on the 1–4-linked mannose, beyond being an essential determinant for Gpi10p, is necessary for an efficient recognition of GPI lipids and GPI proteins by the GPI transamidase for the efficient transport of GPI-anchored proteins from the endoplasmic reticulum to Golgi and for the physiological incorporation of ceramides into GPI anchors by lipid remodeling. Furthermore, mcd4 cells have a marked defect in axial bud site selection, whereas this process is normal in gpi7 and gpi1. This also suggests that axial bud site selection specifically depends on the presence of the ethanolaminephosphate on the 1–4-linked mannose.

Received for publication, February 14, 2006 , and in revised form, May 15, 2006.

^* This work was supported by Swiss National Science Foundation Grant 31-67188.01. 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 Present address: Institute of Live Science and Biotechnology, Hunan University, 410082 Changsha City, China.

² To whom correspondence should be addressed: Div. of Biochemistry, Chemin du Musée 5, CH-1700 Fribourg, Switzerland. Tel.: 41-26-300-8630; Fax: 41-26-300-9735; E-mail: andreas.conzelmann{at}unifr.ch.

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