title: Functional interactions between sphingolipids and sterols in biological membranes regulating cell physiology.
abstract: 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.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore.
authors.forename: Xue Li
authors.initials: XL
authors.lastname: Guan
authors.forename: Cleiton M
authors.initials: CM
authors.lastname: Souza
authors.forename: Harald
authors.initials: H
authors.lastname: Pichler
authors.forename: Gisèle
authors.initials: G
authors.lastname: Dewhurst
authors.forename: Olivier
authors.initials: O
authors.lastname: Schaad
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kajiwara
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Tanya
authors.initials: T
authors.lastname: Ivanova
authors.forename: Guillaume A
authors.initials: GA
authors.lastname: Castillon
authors.forename: Manuele
authors.initials: M
authors.lastname: Piccolis
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Abe
authors.forename: Robbie
authors.initials: R
authors.lastname: Loewith
authors.forename: Kouichi
authors.initials: K
authors.lastname: Funato
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: Howard
authors.initials: H
authors.lastname: Riezman
mesh_terms: D016880:Anisotropy; D001692:Biological Transport / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013011:Sorbic Acid / Q000494:pharmacology; D013107:Sphingolipids / Q000737:chemistry / Q000378:metabolism*; D013261:Sterols / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids; D013261:Sterols; D002110:Caffeine; D020123:Sirolimus; D013011:Sorbic Acid