title: Loss of flotillin expression results in weakened desmosomal adhesion and Pemphigus vulgaris-like localisation of desmoglein-3 in human keratinocytes.
abstract: Desmosomes are adhesion plaques that mediate cell-cell adhesion in many tissues, including the epidermis, and generate mechanical resistance to tissues. The extracellular domains of desmosomal cadherin proteins, desmogleins and desmocollins, are required for the interaction with cadherins of the neighbouring cells, whereas their cytoplasmic tails associate with cytoplasmic proteins which mediate connection to intermediate filaments. Disruption of desmosomal adhesion by mutations, autoantibodies or bacterial toxins results in severe human disorders of e.g. the skin and the heart. Despite the vital role of desmosomes in various tissues, the details of their molecular assembly are not clear. We here show that the two members of the flotillin protein family directly interact with the cytoplasmic tails of desmogleins. Depletion of flotillins in human keratinocytes results in weakened desmosomal adhesion and reduced expression of desmoglein-3, most likely due to a reduction in the desmosomal pool due to increased turnover. In the absence of flotillins, desmoglein-3 shows an altered localisation pattern in the cell-cell junctions of keratinocytes, which is highly similar to the localisation observed upon treatment with pemphigus vulgaris autoantibodies. Thus, our data show that flotillins, which have previously been connected to the classical cadherins, are also of importance for the desmosomal cell adhesion.
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Völlner
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
authors.forename: Jawahir
authors.initials: J
authors.lastname: Ali
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Kurrle
authors.affiliation: Department of Dermatology and Allergology, Philipps University of Marburg, Baldingerstrasse, 35043 Marburg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Exner
authors.affiliation: Department of Dermatology and Allergology, Philipps University of Marburg, Baldingerstrasse, 35043 Marburg, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Eming
authors.affiliation: Department of Dermatology and Allergology, Philipps University of Marburg, Baldingerstrasse, 35043 Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hertl
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Banning
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
authors.forename: Ritva
authors.initials: R
authors.lastname: Tikkanen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051184:Desmoglein 3 / Q000378:metabolism*; D003896:Desmosomes / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010392:Pemphigus / Q000378:metabolism*; D000072417:Protein Domains; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats
chemical_list: D001323:Autoantibodies; D015820:Cadherins; D003598:Cytoskeletal Proteins; C071894:DSG3 protein, human; D051184:Desmoglein 3; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C106354:flotillins