Fig. 7.

Model of perturbed protein homeostasis in DEB. In normal skin, C7 is present and active in the extracellular environment. It may also be sensed intracellularly. In DEB skin, the lack of extracellular C7 leads to the loss of direct and indirect extracellular binding partners, like laminin-332 and integrin α6β4, contributing to increased TGF-β signaling by a loss of repression. Increased TGF-β leads to increased abundance and secretion of cathepsin B, which in turn may further release extracellular TGF-β in a positive feedback mechanism. Increased cathepsin B levels also depend on the presence of C7 by a so far unknown mechanism. In parallel, the levels of inflammatory proteins, like S100A8 and S100A9, are increased. Extracellular cathepsin B may further contribute to DEB pathology by degrading the ECM at the dermal-epidermal junction, e.g. laminin beta-1 and gamma-1 present in laminin 311 and laminin 511, and collagen IV (8), weakening the basement membrane.