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 - 19/04/17
Abstract |
Background |
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). However, not all patients with AD have FLG mutations.
Objective |
We 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.
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. 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.
Conclusion |
Our findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.
El texto completo de este artículo está disponible en PDF.Graphical abstract |
Key words : Atopic dermatitis, skin barrier, filaggrin, regulatory associated protein of the MTOR complex 1, protease
Abbreviations used : AD, AKT1, CTSH, EM, FLG, GAPDH, mTORC1/2, RAPTOR, REK, RXRα, shRNA, SNP, WT
Esquema
| R.F.L.O. is funded by the Great Ormond Street Hospital Children's Charity. A.S.N. is funded by a British Skin Foundation studentship (2018s). C.C. is funded as part of the Centre for Dermatology and Genetic Medicine, University of Dundee Wellcome Trust Strategic Award (098439/Z/12/Z). S.J.B. is supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (106865/Z/15/Z) and a research grant from the Manknell Charitable Trust. |
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| Disclosure of potential conflict of interest: C. Cole's and W. O. Cookson's institutions have received a grant from Wellcome Trust. S. J. Brown's institution has received a grant from Wellcome Trust Senior Research Fellowship in Clinical Science, Tayside Dermatological Research Charity, and Manknell Charitable Trust; has received board memberships from Wellcome Trust and the British Journal of Dermatology; has received consultancy fees from CXR Biosciences; has received payment for lectures from the American Academy of Allergy, Asthma & Immunology; and has submitted a patent application (GB 1602011.7). The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 139 - N° 4
P. 1228-1241 - avril 2017 Regresar al número
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