title: Lipid sorting by ceramide structure from plasma membrane to ER for the cholera toxin receptor ganglioside GM1.
abstract: The glycosphingolipid GM1 binds cholera toxin (CT) on host cells and carries it retrograde from the plasma membrane (PM) through endosomes, the trans-Golgi (TGN), and the endoplasmic reticulum (ER) to induce toxicity. To elucidate how a membrane lipid can specify trafficking in these pathways, we synthesized GM1 isoforms with alternate ceramide domains and imaged their trafficking in live cells. Only GM1 with unsaturated acyl chains sorted efficiently from PM to TGN and ER. Toxin binding, which effectively crosslinks GM1 lipids, was dispensable, but membrane cholesterol and the lipid raft-associated proteins actin and flotillin were required. The results implicate a protein-dependent mechanism of lipid sorting by ceramide structure and provide a molecular explanation for the diversity and specificity of retrograde trafficking by CT in host cells.
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniel J-F
authors.initials: DJ
authors.lastname: Chinnapen
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Hsieh
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: te Welscher
authors.forename: David E
authors.initials: DE
authors.lastname: Saslowsky
authors.forename: Lydia
authors.initials: L
authors.lastname: Kaoutzani
authors.forename: Eelke
authors.initials: E
authors.lastname: Brandsma
authors.forename: Ludovic
authors.initials: L
authors.lastname: D'Auria
authors.forename: Hyejung
authors.initials: H
authors.lastname: Park
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Wagner
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Drake
authors.forename: Minchul
authors.initials: M
authors.lastname: Kang
authors.forename: Thomas
authors.initials: T
authors.lastname: Benjamin
authors.forename: M David
authors.initials: MD
authors.lastname: Ullman
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Costello
authors.forename: Anne K
authors.initials: AK
authors.lastname: Kenworthy
authors.forename: Tobias
authors.initials: T
authors.lastname: Baumgart
authors.forename: Ramiro H
authors.initials: RH
authors.lastname: Massol
authors.forename: Wayne I
authors.initials: WI
authors.lastname: Lencer
mesh_terms: D001692:Biological Transport; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000737:chemistry* / Q000378:metabolism; D002772:Cholera Toxin / Q000737:chemistry* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000737:chemistry* / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D020033:Protein Isoforms / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
chemical_list: D002518:Ceramides; D020033:Protein Isoforms; D005677:G(M1) Ganglioside; D002772:Cholera Toxin