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

Aishath S. Naeem, Cristina Tommasi, Christian Cole, Stuart J. Brown, Yanan Zhu, Benjamin Way, Saffron A. G. Willis Owen, Miriam Moffatt, William O. Cookson, John I. Harper, W. L. Di, Sara J. Brown, Thomas Reinheckel, Ryan F. L. O'Shaughnessy (Lead / Corresponding author)

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1228-1241
Number of pages14
JournalJournal of Allergy and Clinical Immunology
Volume139
Issue number4
Early online date29 Nov 2016
DOIs
Publication statusPublished - Apr 2017

Fingerprint

Cathepsin H
Thymoma
Atopic Dermatitis
Oncogenes
Skin
Keratinocytes
Small Interfering RNA
Peptide Hydrolases
Protein-Serine-Threonine Kinases
Protein Subunits
mechanistic target of rapamycin complex 1
filaggrin
TOR complex 2
Up-Regulation
Cell Culture Techniques
Phenotype
Mutation

Keywords

  • Atopic dermatitis
  • Skin barrier
  • Filaggrin
  • RAPTOR
  • Protease

Cite this

Naeem, Aishath S. ; Tommasi, Cristina ; Cole, Christian ; Brown, Stuart J. ; Zhu, Yanan ; Way, Benjamin ; Willis Owen, Saffron A. G. ; Moffatt, Miriam ; Cookson, William O. ; Harper, John I. ; Di, W. L. ; Brown, Sara J. ; Reinheckel, Thomas ; O'Shaughnessy, Ryan F. L. / 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. In: Journal of Allergy and Clinical Immunology. 2017 ; Vol. 139, No. 4. pp. 1228-1241.
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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, 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.",
keywords = "Atopic dermatitis, Skin barrier, Filaggrin, RAPTOR , Protease",
author = "Naeem, {Aishath S.} and Cristina Tommasi and Christian Cole and Brown, {Stuart J.} and Yanan Zhu and Benjamin Way and {Willis Owen}, {Saffron A. G.} and Miriam Moffatt and Cookson, {William O.} and Harper, {John I.} and Di, {W. L.} and Brown, {Sara J.} and Thomas Reinheckel and O'Shaughnessy, {Ryan F. L.}",
note = "We acknowledge UCL genomics for the gene array hybridisation and subsequent analysis. We thank the Electron Microscopy units of Queen Mary University of London and UCL for the transmission electron microscopy analyses. RO is funded by the Great Ormond Street Hospital Children’s Charity, AN is funded by a British Skin Foundation studentship (2018s). CC is funded as part of the Centre for Dermatology and Genetic Medicine, University of Dundee Wellcome Trust Strategic Award (098439/Z/12/Z). Sara 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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pages = "1228--1241",
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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. / Naeem, Aishath S.; Tommasi, Cristina; Cole, Christian; Brown, Stuart J.; Zhu, Yanan; Way, Benjamin; Willis Owen, Saffron A. G.; Moffatt, Miriam; Cookson, William O.; Harper, John I.; Di, W. L.; Brown, Sara J.; Reinheckel, Thomas; O'Shaughnessy, Ryan F. L. (Lead / Corresponding author).

In: Journal of Allergy and Clinical Immunology, Vol. 139, No. 4, 04.2017, p. 1228-1241.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Naeem, Aishath S.

AU - Tommasi, Cristina

AU - Cole, Christian

AU - Brown, Stuart J.

AU - Zhu, Yanan

AU - Way, Benjamin

AU - Willis Owen, Saffron A. G.

AU - Moffatt, Miriam

AU - Cookson, William O.

AU - Harper, John I.

AU - Di, W. L.

AU - Brown, Sara J.

AU - Reinheckel, Thomas

AU - O'Shaughnessy, Ryan F. L.

N1 - We acknowledge UCL genomics for the gene array hybridisation and subsequent analysis. We thank the Electron Microscopy units of Queen Mary University of London and UCL for the transmission electron microscopy analyses. RO is funded by the Great Ormond Street Hospital Children’s Charity, AN is funded by a British Skin Foundation studentship (2018s). CC is funded as part of the Centre for Dermatology and Genetic Medicine, University of Dundee Wellcome Trust Strategic Award (098439/Z/12/Z). Sara 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.

PY - 2017/4

Y1 - 2017/4

N2 - 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.

AB - 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.

KW - Atopic dermatitis

KW - Skin barrier

KW - Filaggrin

KW - RAPTOR

KW - Protease

U2 - 10.1016/j.jaci.2016.09.052

DO - 10.1016/j.jaci.2016.09.052

M3 - Article

VL - 139

SP - 1228

EP - 1241

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 4

ER -