title: Targeting cholesterol in a liquid-disordered environment by theonellamides modulates cell membrane order and cell shape.
abstract: Roles of lipids in the cell membrane are poorly understood. This is partially due to the lack of methodologies, for example, tool chemicals that bind to specific membrane lipids and modulate membrane function. Theonellamides (TNMs), marine sponge-derived peptides, recognize 3β-hydroxysterols in lipid membranes and induce major morphological changes in cultured mammalian cells through as yet unknown mechanisms. Here, we show that TNMs recognize cholesterol-containing liquid-disordered domains and induce phase separation in model lipid membranes. Modulation of membrane order was also observed in living cells following treatment with TNM-A, in which cells shrank considerably in a cholesterol-, cytoskeleton-, and energy-dependent manner. These findings present a previously unrecognized mode of action of membrane-targeting natural products. Meanwhile, we demonstrated the importance of membrane order, which is maintained by cholesterol, for proper cell morphogenesis.
authors.affiliation: Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Arita
authors.affiliation: Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan. Electronic address: nshin@pharm.kyoto-u.ac.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Lipid Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Ishitsuka
authors.affiliation: Lipid Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Kishimoto
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Ikenouchi
authors.affiliation: Lipid Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Umeda
authors.affiliation: Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsunaga
authors.affiliation: Lipid Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan; JST CREST, Saitama 351-0198, Japan. Electronic address: yoshidam@riken.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D048430:Cell Shape / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D003599:Cytoskeleton / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D011485:Protein Binding; D047232:Theonella / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
chemical_list: D008051:Lipid Bilayers; D008081:Liposomes; D010456:Peptides, Cyclic; D014404:Tubulin; C581283:theonellamide A; D002784:Cholesterol