An mTORC1/AKT1/Cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in Atopic Dermatitis

Publication date: Available online 29 November 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Aishath S. Naeem, Cristina Tommasi, Christian Cole, Stuart J. Brown, Yanan Zhu, Benjamin Way, Saffron AG. Willis Owen, Miriam Moffatt, William O. Cookson, John I. Harper, Di WL, Sara J. Brown, Thomas Reinheckel, Ryan F.L. O'Shaughnessy
BackgroundFilaggrin, encoded by the FLG gene, is an important component of the skin's barrier to the external environment and genetic defects in FLG strongly associate with Atopic Dermatitis (AD). However, not all AD patients have FLG mutations.ObjectiveWe hypothesised that these patients may possess other defects in filaggrin expression and processing, contributing to barrier disruption and AD, and therefore present novel therapeutic targets for this disease.ResultsWe describe the relationship between the mTORC1 protein subunit RAPTOR, the serine/threonine kinase AKT1 and the protease cathepsin H, for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in AD. In keratinocyte cell culture, RAPTOR up-regulation or AKT1 shRNA knockdown reduced the expression of the protease cathepsin H. Skin of cathepsin H-deficient mice and CTSH shRNA knockdown keratinocytes showed reduced filaggrin processing and the mouse showed both impaired skin barrier function and a mild proinflammatory phenotype.ConclusionOur findings highlight a novel, potentially treatable, signalling axis controlling filaggrin expression and processing which is defective in AD.

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Capsule:FLG mutations strongly associate with Atopic Dermatitis (AD). However, not all AD patients have FLG mutations. An mTORC/AKT1 signalling axis controls both filaggrin expression and processing by controlling expression of the protease Cathepsin H.


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