Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation

Xiaolei Ding; Sebastian Willenborg; Wilhelm Bloch; Sara A Wickström; Prerana Wagle; Susanne Brodesser; Axel Roers; Alexander Jais; Jens C Brüning; Michael N Hall; Markus A Rüegg; Sabine A Eming

doi:10.1016/j.jaci.2019.07.033

Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation

J Allergy Clin Immunol. 2020 Jan;145(1):283-300.e8. doi: 10.1016/j.jaci.2019.07.033. Epub 2019 Aug 8.

Authors

Affiliations

¹ Department of Dermatology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
² Department of Dermatology, University of Cologne, Cologne, Germany.
³ Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne, Germany.
⁴ Paul Gerson Unna Group "Skin Homeostasis and Ageing", Max Planck Institute for Biology of Ageing, Cologne, Germany; Helsinki Institute of Life Science, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Wihuri Research Institute, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany.
⁵ Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany.
⁶ Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
⁷ Max Planck Institute for Metabolism Research, Cologne, Germany.
⁸ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany; Max Planck Institute for Metabolism Research, Cologne, Germany.
⁹ Biozentrum, University of Basel, Basel, Switzerland.
¹⁰ Department of Dermatology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany. Electronic address: sabine.eming@uni-koeln.de.

PMID: 31401286
DOI: 10.1016/j.jaci.2019.07.033

Abstract

Background: Perturbation of epidermal barrier formation will profoundly compromise overall skin function, leading to a dry and scaly, ichthyosis-like skin phenotype that is the hallmark of a broad range of skin diseases, including ichthyosis, atopic dermatitis, and a multitude of clinical eczema variants. An overarching molecular mechanism that orchestrates the multitude of factors controlling epidermal barrier formation and homeostasis remains to be elucidated.

Objective: Here we highlight a specific role of mammalian target of rapamycin complex 2 (mTORC2) signaling in epidermal barrier formation.

Methods: Epidermal mTORC2 signaling was specifically disrupted by deleting rapamycin-insensitive companion of target of rapamycin (Rictor), encoding an essential subunit of mTORC2 in mouse epidermis (epidermis-specific homozygous Rictor deletion [Ric^EKO] mice). Epidermal structure and barrier function were investigated through a combination of gene expression, biochemical, morphological and functional analysis in Ric^EKO and control mice.

Results: Ric^EKO newborns displayed an ichthyosis-like phenotype characterized by dysregulated epidermal de novo lipid synthesis, altered lipid lamellae structure, and aberrant filaggrin (FLG) processing. Despite a compensatory transcriptional epidermal repair response, the protective epidermal function was impaired in Ric^EKO mice, as revealed by increased transepidermal water loss, enhanced corneocyte fragility, decreased dendritic epidermal T cells, and an exaggerated percutaneous immune response. Restoration of Akt-Ser473 phosphorylation in mTORC2-deficient keratinocytes through expression of constitutive Akt rescued FLG processing.

Conclusion: Our findings reveal a critical metabolic signaling relay of barrier formation in which epidermal mTORC2 activity controls FLG processing and de novo epidermal lipid synthesis during cornification. Our findings provide novel mechanistic insights into epidermal barrier formation and could open up new therapeutic opportunities to restore defective epidermal barrier conditions.

Keywords: Epidermal barrier; Rictor; epidermal lipid synthesis; filaggrin; ichthyosis; mammalian target of rapamycin complex 2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Epidermis* / immunology
Epidermis* / metabolism
Filaggrin Proteins
Ichthyosis / genetics
Ichthyosis / immunology
Ichthyosis / metabolism
Intermediate Filament Proteins* / genetics
Intermediate Filament Proteins* / immunology
Intermediate Filament Proteins* / metabolism
Lipids* / biosynthesis
Lipids* / genetics
Lipids* / immunology
Mice
Mice, Knockout
Protein Processing, Post-Translational / genetics
Protein Processing, Post-Translational / immunology*
Rapamycin-Insensitive Companion of mTOR Protein* / genetics
Rapamycin-Insensitive Companion of mTOR Protein* / immunology
Signal Transduction / genetics
Signal Transduction / immunology*

Substances

Filaggrin Proteins
Intermediate Filament Proteins
Lipids
Rapamycin-Insensitive Companion of mTOR Protein
rictor protein, mouse