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A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity

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      Abstract

      Epidermal keratin filaments are important components and organizers of the cornified envelope and regulate mitochondrial metabolism by modulating their membrane composition.

      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.

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      Most cited references 122

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      A rapid method of total lipid extraction and purification.

       E G BLIGH,  W. Dyer (1959)
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        DAMPs, PAMPs and alarmins: all we need to know about danger.

         Marco Bianchi (2006)
        Multicellular animals detect pathogens via a set of receptors that recognize pathogen-associated molecular patterns (PAMPs). However, pathogens are not the only causative agents of tissue and cell damage: trauma is another one. Evidence is accumulating that trauma and its associated tissue damage are recognized at the cell level via receptor-mediated detection of intracellular proteins released by the dead cells. The term "alarmin" is proposed to categorize such endogenous molecules that signal tissue and cell damage. Intriguingly, effector cells of innate and adaptive immunity can secrete alarmins via nonclassical pathways and often do so when they are activated by PAMPs or other alarmins. Endogenous alarmins and exogenous PAMPs therefore convey a similar message and elicit similar responses; they can be considered subgroups of a larger set, the damage-associated molecular patterns (DAMPs).
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          Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.

          Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.
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            Author and article information

            Affiliations
            [1 ]Translational Centre for Regenerative Medicine Leipzig, University of Leipzig, 04103 Leipzig, Germany
            [2 ]Institute of Biology, Division of Cell and Developmental Biology, University of Leipzig, 04103 Leipzig, Germany
            [3 ]Interdisciplinary Centre for Bioinformatics, University of Leipzig, 04107 Leipzig, Germany
            [4 ]Department of Environmental Toxicology, University of California, Davis, Davis, CA 95616
            [5 ]Center for Physiology and Pathophysiology, Institute for Vegetative Physiology, University of Cologne, 50931 Cologne, Germany
            [6 ]Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Medical Faculty, University of Cologne, 50931 Cologne, Germany
            [7 ]Department of Dermatology, University of Colorado, Denver, CO 80045
            [8 ]Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Denver, CO 80045
            [9 ]Institute of Molecular and Cellular Anatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany
            [10 ]Center for Molecular Medicine Cologne, 50931 Cologne, Germany
            [11 ]Center for Biotechnology and Biomedicine, 04103 Leipzig, Germany
            Author notes
            Correspondence to Thomas M. Magin: thomas.magin@ 123456uni-leipzig.de

            P. Vijayaraj’s present address is Dept. of Pediatrics, University of California, Los Angeles, Los Angeles, CA 90095.

            [*]

            V. Kumar and J.-E. Bouameur contributed equally to this paper.

            Journal
            J Cell Biol
            J. Cell Biol
            jcb
            jcb
            The Journal of Cell Biology
            The Rockefeller University Press
            0021-9525
            1540-8140
            7 December 2015
            : 211
            : 5
            : 1057-1075
            26644517
            4674273
            201404147
            10.1083/jcb.201404147
            © 2015 Kumar et al.

            This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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