title: A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity.
abstract: Keratin intermediate filaments (KIFs) protect the epidermis against mechanical force, support strong adhesion, help barrier formation, and regulate growth. The mechanisms by which type I and II keratins contribute to these functions remain incompletely understood. Here, we report that mice lacking all type I or type II keratins display severe barrier defects and fragile skin, leading to perinatal mortality with full penetrance. Comparative proteomics of cornified envelopes (CEs) from prenatal KtyI(-/-) and KtyII(-/-)(K8) mice demonstrates that absence of KIF causes dysregulation of many CE constituents, including downregulation of desmoglein 1. Despite persistence of loricrin expression and upregulation of many Nrf2 targets, including CE components Sprr2d and Sprr2h, extensive barrier defects persist, identifying keratins as essential CE scaffolds. Furthermore, we show that KIFs control mitochondrial lipid composition and activity in a cell-intrinsic manner. Therefore, our study explains the complexity of keratinopathies accompanied by barrier disorders by linking keratin scaffolds to mitochondria, adhesion, and CE formation.
authors.affiliation: Translational Centre for Regenerative Medicine Leipzig, University of Leipzig, 04103 Leipzig, Germany Institute of Biology, Division of Cell and Developmental Biology, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Translational Centre for Regenerative Medicine Leipzig, University of Leipzig, 04103 Leipzig, Germany Institute of Biology, Division of Cell and Developmental Biology, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Jamal-Eddine
authors.initials: JE
authors.lastname: Bouameur
authors.affiliation: Translational Centre for Regenerative Medicine Leipzig, University of Leipzig, 04103 Leipzig, Germany Institute of Biology, Division of Cell and Developmental Biology, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Bär
authors.affiliation: Department of Environmental Toxicology, University of California, Davis, Davis, CA 95616.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Rice
authors.affiliation: Center for Physiology and Pathophysiology, Institute for Vegetative Physiology, University of Cologne, 50931 Cologne, Germany.
authors.forename: Hue-Tran
authors.initials: HT
authors.lastname: Hornig-Do
authors.affiliation: Department of Dermatology, University of Colorado, Denver, CO 80045 Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Denver, CO 80045.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Roop
authors.affiliation: Institute of Molecular and Cellular Anatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schwarz
authors.affiliation: Center for Physiology and Pathophysiology, Institute for Vegetative Physiology, University of Cologne, 50931 Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Medical Faculty, University of Cologne, 50931 Cologne, Germany Center for Molecular Medicine Cologne, 50931 Cologne, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.affiliation: Translational Centre for Regenerative Medicine Leipzig, University of Leipzig, 04103 Leipzig, Germany Institute of Biology, Division of Cell and Developmental Biology, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Thiering
authors.affiliation: Institute of Molecular and Cellular Anatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Rudolf E
authors.initials: RE
authors.lastname: Leube
authors.affiliation: Center for Physiology and Pathophysiology, Institute for Vegetative Physiology, University of Cologne, 50931 Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Medical Faculty, University of Cologne, 50931 Cologne, Germany Center for Molecular Medicine Cologne, 50931 Cologne, Germany.
authors.forename: Rudolf J
authors.initials: RJ
authors.lastname: Wiesner
authors.forename: Preethi
authors.initials: P
authors.lastname: Vijayaraj
authors.affiliation: Translational Centre for Regenerative Medicine Leipzig, University of Leipzig, 04103 Leipzig, Germany Institute of Biology, Division of Cell and Developmental Biology, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Christina B
authors.initials: CB
authors.lastname: Brazel
authors.affiliation: Center for Biotechnology and Biomedicine, 04103 Leipzig, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Heller
authors.affiliation: Interdisciplinary Centre for Bioinformatics, University of Leipzig, 04107 Leipzig, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Binder
authors.affiliation: Interdisciplinary Centre for Bioinformatics, University of Leipzig, 04107 Leipzig, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Löffler-Wirth
authors.affiliation: Center for Biotechnology and Biomedicine, 04103 Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Seibel
authors.affiliation: Translational Centre for Regenerative Medicine Leipzig, University of Leipzig, 04103 Leipzig, Germany Institute of Biology, Division of Cell and Developmental Biology, University of Leipzig, 04103 Leipzig, Germany thomas.magin@uni-leipzig.de.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Magin
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D055233:Cornified Envelope Proline-Rich Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D007382:Intermediate Filaments / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D007633:Keratins / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C503806:Arid5b protein, mouse; D055233:Cornified Envelope Proline-Rich Proteins; D004268:DNA-Binding Proteins; D008055:Lipids; D008565:Membrane Proteins; D020543:Proteome; C491983:Sprr2d protein, mouse; C491980:Sprr2h protein, mouse; D014157:Transcription Factors; C064554:loricrin; D007633:Keratins