An mTORC1/AKT1/Cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in Atopic Dermatitis
Naeem AS, Tommasi C, Cole C, Brown SJ, Zhu Y, Way B, Willis Owen SA, Moffatt M, Cookson WO, Harper JI, Wl D, Brown SJ, Reinheckel T, O'Shaughnessy RF.
J Allergy Clin Immunol. online article
We 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 atopic dermatitis. 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.
Our findings highlight a novel, potentially treatable, signalling axis controlling filaggrin expression and processing, which is defective in atopic dermatitis.
