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

• Published in: Journal of allergy and clinical immunology Vol. 139; no. 4; pp. 1228 - 1241
• Main Authors: Naeem, Aishath S., PhD, Tommasi, Cristina, MRes, Cole, Christian, PhD, Brown, Stuart J., PhD, Zhu, Yanan, PhD, Way, Benjamin, MA, BMBCh, MSc, MRCS, Willis Owen, Saffron A.G., DPhil, Moffatt, Miriam, DPhil, Cookson, William O., DPhil, Harper, John I., MBBS, MD, FRCP, FRCPCH, Di, Wei-Li, PhD, Brown, Sara J., MD, FRCPE, Reinheckel, Thomas, PhD, O'Shaughnessy, Ryan F.L., PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.04.2017; Mosby
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Allergy and Immunology; Animals; Arthritis; Atopic Dermatitis and Skin Disease; Blotting, Western; Cathepsin H - deficiency; Cathepsin H - metabolism; Cytokines; Dermatitis; Dermatitis, Atopic - metabolism; Dermatitis, Atopic - pathology; Disruption; Eczema; Filaggrin Proteins; Fluorescent Antibody Technique; Gene expression; Homology; Humans; Immunohistochemistry; Intermediate Filament Proteins - metabolism; Keratinocytes - metabolism; Keratinocytes - pathology; Male; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Mutation; Oligonucleotide Array Sequence Analysis; Oncogenes; Plasmids; Protease; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Rats; Real-Time Polymerase Chain Reaction; Regulatory-Associated Protein of mTOR; Rodents; Signal transduction; Skin - metabolism; Skin - pathology; United Kingdom > UK; FLG; RXRα; mTORC1/2; Mechanistic target of rapamycin complex 1/2; protease; SNP; Atopic dermatitis; shRNA; Filaggrin gene; AKT1; CTSH; filaggrin; Retinoid-X receptor α; WT; skin barrier; AD; Cathepsin H; EM; Electron microscopy; Wild-type; RAPTOR; Glyceraldehyde-3-phosphae dehydrogenase; V-Akt murine thymoma viral oncogene homolog 1; REK; Rat epidermal keratinocyte; Single nucleotide polymorphism; Short hairpin RNA; GAPDH; regulatory associated protein of the MTOR complex 1
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2016.09.052

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.