858 Desmoglein 3 acts as a mechanosensor in keratinocytes

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The desmosomal cadherin, Desmoglein 3 (Dsg3), plays a crucial role in cell-cell cohesion and tissue integrity that is highlighted in the autoimmune blistering disease pemphigus vulgaris where Dsg3 serves as a major autoantigen (PVA). Increasing evidence suggests that Dsg3 acts as a surface regulator in cell mechano-transduction. However, little is known about its direct response to mechanical forces. The aim of this study was to investigate the impact of cyclic strain and substrate stiffness on Dsg3 expression, compared with E-cadherin a well-characterized mechanosensor. Both oral and skin keratinocytes were tested using the Flexcell system and were subjected to mechanical stretching for various time periods. Although no apparent change was found at the mRNA level in response to strain for up to 24 hours, increased protein expression was detectable for Dsg3 and associated junctional proteins (to a lesser extent for E-cadherin). We found that oral keratinocytes appeared to be more mechano-sensitive than skin cells which exhibited a more delayed response. Marked increases of cell-surface Dsg3 and E-cadherin, along with actin-myosin cytoskeleton changes, was detected in strained cells. Conversely Dsg3 depletion had a negative impact on these processes. It was revealed that cyclic strain did not necessarily enhance cell-cell adhesion strength or levels of calcium-independent desmosomes but, instead, exacerbated junction remodeling with accelerated desmoplakin turnover and increased PKCa expression. Significantly, we showed that Dsg3 regulated the expression of YAP, a mechanosensor and an effecter of the Hippo pathway. Dsg3 knockdown resulted in pronounced attenuation of YAP/pYAP in both strained and non-strained cells. Colocalisation of Dsg3 and pYAP was observed at the plasma membrane of cells with their physical interaction being demonstrable by co-IP. Together, our findings strongly suggest a novel role for Dsg3 in keratinocyte mechano-transduction.