Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 134, Issue 9, Pages 2381-2389Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jid.2014.185
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Funding
- Excellence Initiative of the German Federal and State Governments through FRIAS-LifeNet and BIOSS
- German Research Foundation, DFG [BR 1475/12-1, DE 1757/3-1, SFB 850-B8]
- Debra International
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Absence of collagen VII leads to widespread cellular and tissue phenotypes. However, the underlying molecular mechanisms are not well understood. To gain insights into cellular responses to loss of collagen VII, we undertook a quantitative disease proteomics approach. By using recessive dystrophic epidermolysis bullosa (RDEB), a skin blistering disease caused by collagen VII deficiency, as a genetic model, collagen VII-dependent differences in cellular protein abundances and protein-protein interactions were analyzed. Absence of collagen VII led to alterations of intracellular protein compositions and to perturbations in cell adhesion, protein trafficking, and the turnover pathway autophagy. A potential linker of the different cellular phenotypes is transglutaminase 2 (TGM2), a multifunctional enzyme important for protein cross-linking. TGM2 was identified as a stable interaction partner of collagen VII. In RDEB, both abundance and activity of TGM2 were reduced, accounting not only for diminished adhesion and perturbed autophagy but also for reduced cross-linking of the extracellular matrix and for decreased epidermal-dermal integrity in RDEB.
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