Universität zu Köln

Ding, Xiaolei, Willenborg, Sebastian, Bloch, Wilhelm, Wickstroem, Sara A., Wagle, Prerana, Brodesser, Susanne, Roers, Axel, Jais, Alexander ORCID: 0000-0002-9897-4983, Bruening, Jens C., Hall, Michael N., Rueegg, Markus A. and Eming, Sabine A. (2020). Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation. J. Allergy Clin. Immunol., 145 (1). S. 283 - 309. NEW YORK: MOSBY-ELSEVIER. ISSN 1097-6825

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ding, Xiaolei UNSPECIFIED UNSPECIFIED UNSPECIFIED Willenborg, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Bloch, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Wickstroem, Sara A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagle, Prerana UNSPECIFIED UNSPECIFIED UNSPECIFIED Brodesser, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Roers, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Jais, Alexander UNSPECIFIED orcid.org/0000-0002-9897-4983 UNSPECIFIED Bruening, Jens C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hall, Michael N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rueegg, Markus A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Eming, Sabine A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-352266
DOI:	10.1016/j.jaci.2019.07.033
Journal or Publication Title:	J. Allergy Clin. Immunol.
Volume:	145
Number:	1
Page Range:	S. 283 - 309
Date:	2020
Publisher:	MOSBY-ELSEVIER
Place of Publication:	NEW YORK
ISSN:	1097-6825
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language STRATUM-CORNEUM BARRIER; OF-FUNCTION MUTATIONS; CAUSE ICHTHYOSIS; STEM-CELLS; T-CELLS; IN-VIVO; DIFFERENTIATION; AKT; EXPRESSION; ABNORMALITIES Multiple languages Allergy; Immunology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/35226