A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

Aishath S Naeem,Cristina Tommasi,Christian Cole,Stuart J Brown,Yanan Zhu,Benjamin Way,Saffron A.G Willis Owen,Miriam Moffatt,William O Cookson,John I Harper,Wei-Li Di,Sara J Brown,Thomas Reinheckel,Ryan F.L O'Shaughnessy

doi:10.1016/j.jaci.2016.09.052

Abstract

BackgroundFilaggrin, which is encoded by the filaggrin gene (FLG), 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 patients with AD have FLG mutations.ObjectiveWe hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and therefore we present novel therapeutic targets for this disease.ResultsWe describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in patients with AD. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype.ConclusionOur findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.

Highlights

Filaggrin, which is encoded by the filaggrin gene (FLG), is an important component of the skin’s barrier to the external environment, and genetic defects in FLG strongly associate with atopic dermatitis (AD)
We describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/ threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing
Because inhibition of the mechanistic target of rapamycin complex 1/2 (mTORC1) complex by rapamycin increases AKT1 phosphorylation in keratinocytes,[18] we hypothesized that the inverse could occur and that increased expression of the key mTORC1 protein RAPTOR in patients with AD would result in a reduction of AKT1 phosphorylation and activity

Summary

Introduction

Filaggrin, which is encoded by the filaggrin gene (FLG), is an important component of the skin’s barrier to the external environment, and genetic defects in FLG strongly associate with atopic dermatitis (AD). Objective: We hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and we present novel therapeutic targets for this disease. Results: We describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/ threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype. Conclusion: Our findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD. (J Allergy Clin Immunol 2017;139:1228-41.)

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