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

Keywords

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

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