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Vol. 20, Issue 7, 2083-2095, April 1, 2009

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Functional Interactions between Sphingolipids and Sterols in Biological Membranes Regulating Cell Physiology

Xue Li Guan^*,, Cleiton M. Souza^,, Harald Pichler^,,, Gisèle Dewhurst, Olivier Schaad, Kentaro Kajiwara^||, Hirotomo Wakabayashi^||, Tanya Ivanova, Guillaume A. Castillon, Manuele Piccolis^¶, Fumiyoshi Abe^#, Robbie Loewith^¶, Kouichi Funato^,||, Markus R. Wenk^*, and Howard Riezman

*Department of Biochemistry and Department of Biological Sciences, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore; Departments of Biochemistry, and ^¶Molecular Biology, University of Geneva, CH-1211 Geneva, Switzerland; Institute of Molecular Biotechnology, Graz University of Technology, A-8010 Graz, Austria; ^||Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan; and ^#Extremobiosphere Research Center, Japan Agency for Marine-Earth Science and Technology, Yokosuka 237-0061, Japan

Submitted November 17, 2008; Revised January 28, 2009; Accepted February 5, 2009
Monitoring Editor: Benjamin S. Glick

InCytes from MBC

Sterols and sphingolipids are limited to eukaryotic cells, and their interaction has been proposed to favor formation of lipid microdomains. Although there is abundant biophysical evidence demonstrating their interaction in simple systems, convincing evidence is lacking to show that they function together in cells. Using lipid analysis by mass spectrometry and a genetic approach on mutants in sterol metabolism, we show that cells adjust their membrane composition in response to mutant sterol structures preferentially by changing their sphingolipid composition. Systematic combination of mutations in sterol biosynthesis with mutants in sphingolipid hydroxylation and head group turnover give a large number of synthetic and suppression phenotypes. Our unbiased approach provides compelling evidence that sterols and sphingolipids function together in cells. We were not able to correlate any cellular phenotype we measured with plasma membrane fluidity as measured using fluorescence anisotropy. This questions whether the increase in liquid order phases that can be induced by sterol–sphingolipid interactions plays an important role in cells. Our data revealing that cells have a mechanism to sense the quality of their membrane sterol composition has led us to suggest that proteins might recognize sterol–sphingolipid complexes and to hypothesize the coevolution of sterols and sphingolipids.

These authors contributed equally to this work.

Co-senior authors; address correspondence to: Markus R. Wenk (bchmrw{at}nus.edu.sg) or Howard Riezman (howard.riezman{at}unige.ch)