An interacting network of physicians and researchers discovered that activation of the mammalian Target of Rapamycin Complex 2 (mTORC2) in the outermost layer of the skin is critical to protect the skin from dehydration, inflammation and increased allergen sensitivity. The group found that mTORC2 controls lipid metabolism and filaggrin processing both essential processes to ensure the protective function of the skin.
Dry and scaly skin - a hallmark of a broad range of skin diseases
Dry and scaly skin is a hallmark of a broad range of clinical eczema variants associated for example with atopic dermatitis, diabetes mellitus or ageing. Itch, inflammation and infections are frequent symptoms of eczema that negatively affect quality of life, and patients are at high risk for associated morbidity and mortality. The molecular mechanisms causing eczema are not yet understood and were the aim of this study.
mTOR – a nutrient sensitive pathway regulating skin function
The protein kinase mammalian Target of Rapamycin (mTOR) is the central element of an evolutionarily conserved nutrient signalling pathway involved in a wide variety of biological processes, such as energy homeostasis, protein synthesis, growth and ageing. Reducing the activity of mTOR signalling genetically or by pharmaceutical intervention can extend lifespan in many species and delay or prevent ageing-related diseases.
On the other hand, the Eming group and collaborators showed earlier that reduced mTOR signalling activity can also impair specific aspects of health, notably wound healing. It is therefore important to identify the mechanisms that mediate both the health benefits and impairments resulting from reduced mTOR activity.
In the current study, a collaboration between Prof. Sabine Eming, the postdoctoral scientist Dr. Xiaolei Ding and additional international experts in mTOR biology, cell metabolism and immunology identified mTORC2-mediated phosphorylation of Akt-Ser473 as important signalling relay maintaining and repairing the epidermal barrier.
“Altered mTORC2 activity may represent a predisposing factor for a broad range of skin diseases with impaired barrier function, including ichthyosis, atopic dermatitis, and a multitude of clinical eczema variants associated for example with type 2 diabetes or ageing. Our findings could suggest a new therapeutic strategy to restore perturbed epidermal barrier function and to prevent complications in patients with dry skin diseases," Sabine Eming, head of the international research study, underscores.
“Genetically engineered mice lacking mTORC2 activity specifically in the epidermis (RicEKO mouse) develop an ichthyosis-like phenotype and might serve as a new preclinical disease model for studying epidermal barrier defects at the molecular level," Xiaolei Ding, first author of the publication, points out.
Several pharmaceutical companies are developing new drugs to control mTOR activity, which will hopefully help to treat patients suffering from impaired skin barrier function.
Epidermal mTORC2 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. J Allergy Clin Immunol (in press)
Prof. Dr. med. Sabine Eming
Professor of Dermatology, University Hospital Cologne and Principle Investigator at the Center for Molecular Medicine Cologne, University of Cologne