Imbalance of intermediate filament component keratin 14 contributes to increased stress signalling in epidermolysis bullosa simplex

An important characteristic of epidermolysis bullosa simplex D owling– M eara ( EBS‐DM ) keratinocytes is the increased level of Jun N ‐terminal kinase ( JNK ) stress signalling, which is thought to contribute to the disease phenotype. In this work, we report on the dramatic up‐regulation of cytokeratin 14 ( K 14) in the EBS‐DM model cell line KEB 7 at both the transcriptional and translational levels, which is noteworthy because KEB 7 patient cells are heterozygous for a missense mutation ( R 125 P ) in K 14. By performing functional assays, we show a direct link between overexpressed wild‐type K 14 and increased JNK signalling in healthy, immortalized keratinocytes. This observation led us to hypothesize a positive feedback model in which mutant ( R 125 P ) K 14 triggers JNK signalling, leading to increased AP 1‐dependent expression of K 14, which in turn amplifies JNK signalling further. We therefore suggest that an imbalance of cytoplasmic K 14 monomers and K 14 incorporated into the intermediate filament ( IF ) network leads to elevated stress signalling, potentially altering IF dynamics by phosphorylation, which as a side effect, weakens EBS‐DM keratinocytes.