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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

O'Shaughnessy, RFL; Naeem, A; Tommasi, C; Brown, S; Zhu, Y; Way, B; Harper, J; (2016) 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. Journal of Allergy and Clinical Immunology , 139 (4) pp. 1228-1241. 10.1016/j.jaci.2016.09.052. Green open access

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Abstract

BACKGROUND: Filaggrin, 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. OBJECTIVE: We 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. RESULTS: 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 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. CONCLUSION: Our findings highlight a novel, potentially treatable, signalling axis controlling filaggrin expression and processing which is defective in AD.

Type: Article
Title: 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
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jaci.2016.09.052
Publisher version: https://doi.org/10.1016/j.jaci.2016.09.052
Language: English
Additional information: Copyright © 2016 The Authors. Published by Elsevier Inc. on behalf of the American Academyof Allergy, Asthma & Immunology. This is an open access article under the CC BYlicense (http://creativecommons.org/licenses/by/4.0/).
Keywords: Atopic dermatitis, skin barrier, filaggrin, regulatory associated protein of the MTOR complex 1, protease
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1524221
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