P09 Characterizing defective Hippo/Yes-associated protein/TAZ signalling in junctional epidermolysis bullosa

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ID: 318477
2026
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Abstract
Abstract Introduction and aims Junctional epidermolysis bullosa (JEB) is a severe skin blistering disease with impaired wound healing and high infection risk, caused by defects in laminin-332. The transcriptional coregulators Yes-associated protein (YAP)/TAZ are important for long-term self-renewal of epidermal stem cells. They are negatively regulated by the Hippo signalling pathway. Dysregulated YAP/TAZ activity in JEB skin was previously shown to decrease epidermal keratinocyte proliferation and tissue repair. This project aims to characterize the defective signalling mechanism that cause dysfunction of YAP/TAZ in JEB epidermis. Methods Immortalized N/TERT-1 keratinocytes with short hairpin RNA-mediated laminin-332 knockdown were evaluated as alternative in vitro models to replace primary JEB keratinocytes, using clonal growth assays, Western blot analysis, and reverse transcriptase quantitative polymerase chain reaction. Results LAMA3-depleted N/TERT-1 cells displayed reduced clonal growth, thus recapitulating a key phenotype of primary JEB keratinocytes. Cell density-dependent activation of the Hippo pathway was confirmed in parental N/TERT-1 keratinocytes. High cell density caused activation of the core Hippo kinase cascade, leading to inactivating phosphorylation of YAP, and decreased mRNA expression of YAP/TAZ target genes. LAMA3 knockdown in N/TERT-1 cells caused reduced expression of YAP at mRNA and protein level, along with reduced levels of YAP/TAZ target genes CCN1 and ANKRD1. Conclusions Our findings suggest that LAMA3-depleted N/TERT-1 keratinocytes recapitulate key features of primary JEB keratinocytes, supporting their use as an in vitro model for studying YAP/TAZ dysregulation in JEB. The observed decrease in YAP expression at both mRNA and protein levels indicates laminin-332-dependent regulation of YAP. Although preliminary, these results highlight a promising path for uncovering mechanisms underlying impaired Hippo/YAP/TAZ signalling in laminin-332-deficient keratinocytes and for guiding future therapeutic strategies. Next, we will test small-molecule YAP/TAZ activators in two-dimensional and three-dimensional organotypic cultures and in a JEB mouse model to evaluate whether they can restore normal YAP/TAZ activity in JEB skin.
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Authors Ilaria di Girolamo, Viktorija Lapinska, Leonor Ferreira Lopes, Elodie Sins, Matthew Caley, Emanuel Rognoni, Gernot Walko
Journal the british journal of dermatology
Year 2026
DOI
10.1093/bjd/ljag151.050
URL
https://doi.org/10.1093/bjd/ljag151.050
Keywords Keywords not found

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