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.
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.
  
  
  CONCLUSIONS
  Our findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, United Kingdom; Livingstone Skin Research Centre, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Aishath S
authors.initials: AS
authors.lastname: Naeem
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, United Kingdom; Livingstone Skin Research Centre, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tommasi
authors.affiliation: Computational Biology, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Cole
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, United Kingdom; Livingstone Skin Research Centre, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Brown
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, United Kingdom; Livingstone Skin Research Centre, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, United Kingdom; Livingstone Skin Research Centre, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Way
authors.affiliation: National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Saffron A G
authors.initials: SA
authors.lastname: Willis Owen
authors.affiliation: National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Miriam
authors.initials: M
authors.lastname: Moffatt
authors.affiliation: National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: William O
authors.initials: WO
authors.lastname: Cookson
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, United Kingdom; Livingstone Skin Research Centre, UCL Institute of Child Health, London, United Kingdom.
authors.forename: John I
authors.initials: JI
authors.lastname: Harper
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, United Kingdom; Livingstone Skin Research Centre, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Di
authors.affiliation: Centre for Dermatology and Genetic Medicine, Medical Research Institute, University of Dundee, Dundee, United Kingdom.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Brown
authors.affiliation: Institute of Molecular Medicine and Cell Research, BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, United Kingdom; Livingstone Skin Research Centre, UCL Institute of Child Health, London, United Kingdom. Electronic address: r.oshaughnessy@ucl.ac.uk.
authors.forename: Ryan F L
authors.initials: RF
authors.lastname: O'Shaughnessy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D056655:Cathepsin H / Q000172:deficiency / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000378:metabolism* / Q000473:pathology; D000091344:Filaggrin Proteins; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D020411:Oligonucleotide Array Sequence Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D000076223:Regulatory-Associated Protein of mTOR; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C534126:CTSH protein, human; D056655:Cathepsin H; C534127:Ctsh protein, mouse
keywords: Atopic dermatitis; filaggrin; protease; regulatory associated protein of the MTOR complex 1; skin barrier