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Combinatorial omics analysis reveals perturbed lysosomal homeostasis in collagen VII-deficient keratinocytes

  • Thriene, Kerstin Department of Dermatology, Medical Center - University of Freiburg, Germany
  • Grüning, Björn Andreas Department of Dermatology, Medical Center - University of Freiburg, Germany
  • Bornert, Olivier Department of Dermatology, Medical Center - University of Freiburg, Germany
  • Erxleben, Anika Department of Dermatology, Medical Center - University of Freiburg, Germany
  • Leppert, Juna Department of Dermatology, Medical Center - University of Freiburg, Germany
  • Athanasiou, Ioannis Department of Dermatology, Medical Center - University of Freiburg, Germany
  • Weber, Ekkehard Centre for Biological Systems Analysis (ZBSA), University of Freiburg, Germany
  • Kiritsi, Dimitra Department of Dermatology, Medical Center - University of Freiburg, Germany
  • Nyström, Alexander Department of Dermatology, Medical Center - University of Freiburg, Germany
  • Reinheckel, Thomas Department of Computer Science, University of Freiburg, Germany
  • Backofen, Rolf Department of Dermatology, Medical Center - University of Freiburg, Germany
  • Has, Cristina Institute of Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg, Germany
  • Bruckner-Tuderman, Leena Department of Dermatology, Medical Center - University of Freiburg, Germany
  • Dengjel, Jörn Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Germany
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    11.01.2018
Published in:
  • Molecular & Cellular Proteomics. - 2018, vol. 17, no. 4, p. 565-579
English The extracellular matrix protein collagen VII is part of the microenvironment of stratified epithelia and critical in organismal homeostasis. Mutations in the encoding gene COL7A1 lead to the skin disorder dystrophic epidermolysis bullosa (DEB), are linked to skin fragility and progressive inflammation-driven fibrosis that facilitates aggressive skin cancer. So far, these changes have been linked to mesenchymal alterations, the epithelial consequences of collagen VII loss remaining under- addressed. As epithelial dysfunction is a principal initiator of fibrosis, we performed a comprehensive transcriptome and proteome profiling of primary human keratinocytes to generate global and detailed images of dysregulated epidermal molecular pathways linked to loss of collagen VII. These revealed downregulation of interaction partners of collagen VII on mRNA and protein level, but also increased abundance of S100 pro- inflammatory proteins in primary DEB keratinocytes. Increased TGF-β signaling due to loss of collagen VII was associated with enhanced activity of lysosomal proteases in both keratinocytes and skin of collagen VII-deficient individuals. Thus, loss of a single structural protein, collagen VII, has extra- and intracellular consequences, resulting in inflammatory processes that enable tissue destabilization and promote keratinocyte- driven, progressive fibrosis.
Faculty
Faculté des sciences et de médecine
Department
Département de Biologie
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/306229
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