title: Bile acids modulate signaling by functional perturbation of plasma membrane domains.
abstract: Eukaryotic cell membranes are organized into functional lipid and protein domains, the most widely studied being membrane rafts. Although rafts have been associated with numerous plasma membrane functions, the mechanisms by which these domains themselves are regulated remain undefined. Bile acids (BAs), whose primary function is the solubilization of dietary lipids for digestion and absorption, can affect cells by interacting directly with membranes. To investigate whether these interactions affected domain organization in biological membranes, we assayed the effects of BAs on biomimetic synthetic liposomes, isolated plasma membranes, and live cells. At cytotoxic concentrations, BAs dissolved synthetic and cell-derived membranes and disrupted live cell plasma membranes, implicating plasma membrane damage as the mechanism for BA cellular toxicity. At subtoxic concentrations, BAs dramatically stabilized domain separation in Giant Plasma Membrane Vesicles without affecting protein partitioning between coexisting domains. Domain stabilization was the result of BA binding to and disordering the nonraft domain, thus promoting separation by enhancing domain immiscibility. Consistent with the physical changes observed in synthetic and isolated biological membranes, BAs reorganized intact cell membranes, as evaluated by the spatial distribution of membrane-anchored Ras isoforms. Nanoclustering of K-Ras, related to nonraft membrane domains, was enhanced in intact plasma membranes, whereas the organization of H-Ras was unaffected. BA-induced changes in Ras lateral segregation potentiated EGF-induced signaling through MAPK, confirming the ability of BAs to influence cell signal transduction by altering the physical properties of the plasma membrane. These observations suggest general, membrane-mediated mechanisms by which biological amphiphiles can produce their cellular effects.
authors.affiliation: From the Department of Integrative Biology and Pharmacology, the University of Texas Medical School, Houston, Texas 77030 and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Kelsey N
authors.initials: KN
authors.lastname: Maxwell
authors.forename: Erdinc
authors.initials: E
authors.lastname: Sezgin
authors.forename: Maryia
authors.initials: M
authors.lastname: Lu
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Dial
authors.forename: Lenard M
authors.initials: LM
authors.lastname: Lichtenberger
authors.forename: Ilya
authors.initials: I
authors.lastname: Levental
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D003840:Deoxycholic Acid / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008823:Micelles; D049329:Nanostructures / Q000737:chemistry; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D012995:Solubility; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D008081:Liposomes; D008565:Membrane Proteins; D008823:Micelles; D003840:Deoxycholic Acid; D018631:ras Proteins
keywords: Bile Acid; Lipid Raft; Membrane Bilayer; Membrane Biophysics; Membrane Lipids; Membrane Structure; Ras