Combinatorial Omics Analysis Reveals Perturbed Lysosomal Homeostasis in Collagen VII-deficient Keratinocytes.

Abstract

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 from DEB and control subjects 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 because of 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.

• Authors: Kerstin Thriene, Björn Andreas Grüning, Olivier Bornert, Anika Erxleben, Juna Leppert, Ioannis Athanasiou, Ekkehard Weber, Dimitra Kiritsi, Alexander Nyström, Thomas Reinheckel, Rolf Backofen, Cristina Has, Leena Bruckner-Tuderman, Jörn Dengjel
• Journal: Molecular & cellular proteomics : MCP (Mol Cell Proteomics) Vol. 17 Issue 4 Pg. 565-579 (04 2018) ISSN: 1535-9484 [Electronic] United States
• PMID: 29326176 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• COL7A1 protein, human
• Collagen Type VII
• Proteome

Topics

• Cells, Cultured
• Collagen Type VII (genetics, metabolism)
• Homeostasis
• Humans
• Keratinocytes (metabolism)
• Lysosomes (metabolism)
• Mutation
• Proteome
• Transcriptome