The Pemphigus Vulgaris antigen desmoglein-3 suppresses p53 function via the YAP-Hippo pathway

Wan, H.; Rehman, A.; Cai, Y.; Hünefeld, C.; Jedlickova, H.; Huang, Y.; Teh, M.-T.; Uttagomol, J.; Kang, A.; Warnes, G.; Ahmad, U.; Harwood, C. A.; Bergamaschi, D.; Parkinson, E. K.; Röcken, M.; Hart, I. R.

doi:10.1101/399980

bioRxiv · 10.1101/399980

The Pemphigus Vulgaris antigen desmoglein-3 suppresses p53 function via the YAP-Hippo pathway

Wan, H.·Rehman, A.·Cai, Y.·Hünefeld, C.·Jedlickova, H.·Huang, Y.·Teh, M.-T.·Uttagomol, J.·Kang, A.·Warnes, G.·Ahmad, U.·Harwood, C. A.·Bergamaschi, D.·Parkinson, E. K.·Röcken, M.·Hart, I. R.

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Abstract

Desmoglein-3 (Dsg3), the Pemphigus Vulgaris (PV) antigen (PVA), plays an essential role in keratinocyte cell-cell adhesion and regulates various signaling pathways implicated in the pathogenesis the PV blistering disease. We show here that expression of Dsg3 may directly influence p53, a key transcription factor governing the response to cellular stress. Dsg3 depletion caused increased p53 and apoptosis, an effect that was further enhanced by UV and mechanical strain and reversed by Dsg3 gain-of-function studies. Analysis in Dsg3-/- mouse skin confirmed increased p53/p21/caspase-3 compared to Dsg3+/- control in vivo. This Dsg3-p53 pathway involved YAP since Dsg3 forms a complex with YAP and regulates its expression and localization. Analysis of PV patient samples detected increased p53/YAP with diffuse cytoplasmic and/or nuclear staining in cells surrounding blisters. Treatment of keratinocytes with PV sera evoked pronounced p53/YAP expression. Collectively, our findings establish a novel role for Dsg3 as an anti-stress protein, via suppression of p53 function, suggesting that this pathway, involving YAP-Hippo control of skin homeostasis, is disrupted in PV.

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Wan, H., Rehman, A., Cai, Y., Hünefeld, C., Jedlickova, H., Huang, Y., Teh, M.-T., Uttagomol, J., Kang, A., Warnes, G., Ahmad, U., Harwood, C. A., Bergamaschi, D., Parkinson, E. K., Röcken, M., Hart, I. R.. 2018-08-25. The Pemphigus Vulgaris antigen desmoglein-3 suppresses p53 function via the YAP-Hippo pathway. https://doi.org/10.1101/399980

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