Keratin 76 is required for tight junction function and maintenance of the skin barrier
| Autor: | Pritinder Kaur, Denny L Cottle, Patrick O. Humbert, Ian M. Smyth, Tia DiTommaso, Helen B. Pearson, Holger Schlüter |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Keratinocytes
Embryology Genetic Screens Cancer Research Organogenesis Gene Identification and Analysis Intermediate Filaments Epithelium Mice 0302 clinical medicine Molecular Cell Biology Claudin-1 Keratin Intermediate filament Cytoskeleton Integral membrane protein Genetics (clinical) chemistry.chemical_classification 0303 health sciences Tight junction integumentary system Animal Models Phenotype Cell biology 030220 oncology & carcinogenesis Keratins Anatomy Cellular Types Research Article lcsh:QH426-470 Adhesion Molecules Intermediate filament cytoskeleton Mouse Models Biology Research and Analysis Methods Skin Diseases Tight Junctions 03 medical and health sciences Model Organisms Genetics Animals Humans Psoriasis Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Biology and Life Sciences Epithelial Cells Cell Biology Molecular Development lcsh:Genetics Biological Tissue chemistry Mutagenesis Genetics of Disease Mutation Epidermis Wound healing Organism Development Animal Genetics Developmental Biology |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 10, Iss 10, p e1004706 (2014) |
| ISSN: | 1553-7390 |
| Popis: | Keratins are cytoskeletal intermediate filament proteins that are increasingly being recognised for their diverse cellular functions. Here we report the consequences of germ line inactivation of Keratin 76 (Krt76) in mice. Homozygous disruption of this epidermally expressed gene causes neonatal skin flaking, hyperpigmentation, inflammation, impaired wound healing, and death prior to 12 weeks of age. We show that this phenotype is associated with functionally defective tight junctions that are characterised by mislocalization of the integral protein CLDN1. We further demonstrate that KRT76 interacts with CLDN1 and propose that this interaction is necessary to correctly position CLDN1 in tight junctions. The mislocalization of CLDN1 has been associated in various dermopathies, including the inflammatory disease, psoriasis. These observations establish a previously unknown connection between the intermediate filament cytoskeleton network and tight junctions and showcase Krt76 null mice as a possible model to study aberrant tight junction driven skin diseases. Author Summary The generation of knockout mice is a central approach to studying gene function. We have examined the consequences of the germ line inactivation of Keratin 76 in mice and in doing so we reveal a previously undescribed mechanism by which keratin intermediate filaments regulate cellular interactions and tissue homeostasis. Our study supports an emerging body of evidence which challenges the classical view of the keratin intermediate filaments as simple structural proteins, highlighting Krt76 as a gene whose function is indispensable for barrier function and skin wound repair as a result of its novel interaction with tight junction complexes. This study identifies a previously unknown and critical link between intermediate filaments and tight junctions where intermediate filament dysfunction influences skin disease. |
| Databáze: | OpenAIRE |
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