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
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 hypothe...
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Published in | Journal of allergy and clinical immunology Vol. 139; no. 4; pp. 1228 - 1241 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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01.04.2017
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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. |
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AbstractList | 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.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.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.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.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.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.Our findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.CONCLUSIONOur findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD. 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. 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. 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. 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. Our findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD. 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 inFLGstrongly associate with atopic dermatitis (AD). However, not all patients with AD haveFLGmutations. 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. |
Author | Naeem, Aishath S., PhD Way, Benjamin, MA, BMBCh, MSc, MRCS Zhu, Yanan, PhD Harper, John I., MBBS, MD, FRCP, FRCPCH Di, Wei-Li, PhD Reinheckel, Thomas, PhD Tommasi, Cristina, MRes Brown, Sara J., MD, FRCPE Cookson, William O., DPhil Willis Owen, Saffron A.G., DPhil Moffatt, Miriam, DPhil Cole, Christian, PhD Brown, Stuart J., PhD O'Shaughnessy, Ryan F.L., PhD |
AuthorAffiliation | f Institute of Molecular Medicine and Cell Research, BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany a Immunobiology and Dermatology, UCL Institute of Child Health, London, United Kingdom c Computational Biology, School of Life Sciences, University of Dundee, Dundee, United Kingdom e Centre for Dermatology and Genetic Medicine, Medical Research Institute, University of Dundee, Dundee, United Kingdom b Livingstone Skin Research Centre, UCL Institute of Child Health, London, United Kingdom d National Heart and Lung Institute, Imperial College, London, United Kingdom |
AuthorAffiliation_xml | – name: d National Heart and Lung Institute, Imperial College, London, United Kingdom – name: f Institute of Molecular Medicine and Cell Research, BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany – name: a Immunobiology and Dermatology, UCL Institute of Child Health, London, United Kingdom – name: e Centre for Dermatology and Genetic Medicine, Medical Research Institute, University of Dundee, Dundee, United Kingdom – name: b Livingstone Skin Research Centre, UCL Institute of Child Health, London, United Kingdom – name: c Computational Biology, School of Life Sciences, University of Dundee, Dundee, United Kingdom |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27913303$$D View this record in MEDLINE/PubMed |
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Keywords | 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 |
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Snippet | 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... 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... 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... |
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SubjectTerms | 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 |
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 |
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