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

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

doi:10.1016/j.jaci.2019.07.033

Cited by 30 publications

(30 citation statements)

References 71 publications

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“…S4). Changes in the metabolites involved in the BCAA pathway are known to influence the regulation of mTOR 23,24 , which plays a vital role in epidermal barrier formation and the signaling axis for the control of filaggrin as the fundamental pathophysiology of AD [25][26][27][28] . Third, propyl-paraben exposure is associated with aeroallergen sensitization and increased EASI score via the peroxisome proliferator-activated receptors (PPAR) pathway, which is based on decreased levels of palmitic acid and 2-palmitoylglycerol found in our study 29,30 .…”

Section: Discussionmentioning

confidence: 99%

The potential pathways underlying the association of propyl-paraben exposure with aeroallergen sensitization and EASI score using metabolomics analysis

Lee

Yon

et al. 2021

Sci Rep

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Propyl-paraben exposure is associated with aeroallergen sensitization, but its association with atopic dermatitis (AD) is inconclusive. No studies have been conducted on the metabolomic pathways underlying these associations. We investigated the associations between propyl-paraben exposure and aeroallergen sensitization, AD, and Eczema Area and Severity Index (EASI) score and identified the underlying pathways using untargeted metabolomics analysis. We enrolled 455 children in a general population study. Skin prick tests were performed with the assessment of EASI score. Urinary propyl-, butyl-, ethyl-, and methyl-paraben levels were measured. Untargeted metabolomics analysis was performed on the first and fifth urine propyl-paraben quintile groups. The highest urine propyl-paraben quintile group was associated with aeroallergen sensitization, but not with AD. Glycine, threonine, serine, ornithine, isoleucine, arabinofuranose, d-lyxofuranose, citrate, and picolinic acid levels were higher, whereas palmitic acid and 2-palmitoylglycerol levels were lower in the highest quintile propyl-paraben group, than in the lowest quintile group. The propyl-paraben-induced metabolic perturbations were associated with serine and glycine metabolisms, branched-chain amino acid metabolism, and ammonia recycling. Propyl-paraben exposure was associated with aeroallergen sensitization and EASI score, partially via metabolomic changes related with oxidative stress, mTOR, peroxisome proliferator-activated receptors pathway, aryl hydrocarbon receptor signaling pathways, and tricarboxylic acid cycle.

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Section: Discussionmentioning

confidence: 99%

The potential pathways underlying the association of propyl-paraben exposure with aeroallergen sensitization and EASI score using metabolomics analysis

Lee

Yon

et al. 2021

Sci Rep

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“…Recent evidence has demonstrated the mTOR role in epidermal stratification and cornification. Indeed, Ding and colleagues, have shown that mTORC2 controls FLG processing and de novo epidermal lipid synthesis during cornification in mice lacking RICTOR in the epidermis (113). Furthermore, increased transcriptional levels of the regulatory-associated protein of mTORC1, RAPTOR, correlate with decreased FLG expression, barrier defects and presence of inflammatory markers in skin of patients with AD (114).…”

Section: Dual Effects Of Pi3k Pathways In Inflammatory and Hyperproliferative Skin Diseasesmentioning

confidence: 99%

Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

2021

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PhosphoInositide-3 Kinase (PI3K) represents a family of different classes of kinases which control multiple biological processes in mammalian cells, such as cell growth, proliferation, and survival. Class IA PI3Ks, the main regulators of proliferative signals, consists of a catalytic subunit (α, β, δ) that binds p85 regulatory subunit and mediates activation of AKT and mammalian Target Of Rapamycin (mTOR) pathways and regulation of downstream effectors. Dysregulation of PI3K/AKT/mTOR pathway in skin contributes to several pathological conditions characterized by uncontrolled proliferation, including skin cancers, psoriasis, and atopic dermatitis (AD). Among cutaneous cancers, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) display PI3K/AKT/mTOR signaling hyperactivation, implicated in hyperproliferation, and tumorigenesis, as well as in resistance to apoptosis. Upregulation of mTOR signaling proteins has also been reported in psoriasis, in association with enhanced proliferation, defective keratinocyte differentiation, senescence-like growth arrest, and resistance to apoptosis, accounting for major parts of the overall disease phenotypes. On the contrary, PI3K/AKT/mTOR role in AD is less characterized, even though recent evidence demonstrates the relevant function for mTOR pathway in the regulation of epidermal barrier formation and stratification. In this review, we provide the most recent updates on the role and function of PI3K/AKT/mTOR molecular axis in the pathogenesis of different hyperproliferative skin disorders, and highlights on the current status of preclinical and clinical studies on PI3K-targeted therapies.

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“…Previous studies by Ding et al 10 demonstrated that mTOR signaling is indispensable for epidermal barrier formation, 9 although with differential roles defined for mTORC1 and mTORC2. By crossing mice carrying loxP-flanked target alleles (Mtor fl/fl , Rptor fl/fl , or Rictor fl/fl ) with human keratin 14 Cre recombinase transgenic mice, Ding et al 10 were able to respectively abolish complete mTOR signaling, mTORC1 activation, or mTORC2 activation specifically in the epidermis. 9 Deletion of Mtor in mouse epidermis (mTOR EKO ) resulted in newborns with defective epidermal barrier function that succumb to death shortly after birth.…”

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confidence: 99%

“…Recent studies have revealed that mTORC1 is crucial for keratinocyte proliferation and the early epidermal differentiation program. 9 In this issue of the Journal of Allergy and Clinical Immunology, Ding et al 10 show that mTORC2 signaling controls the terminal differentiation and function of keratinocytes in the late stage of epidermal barrier formation (Fig 1).…”

mentioning

confidence: 99%

“…9 In the current study Ding et al 10 follow up on their initial findings with more detailed experiments investigating the precise mechanism by which mTORC2 regulates epidermal barrier formation. Using Ric EKO mice, Ding et al 10 demonstrate that disruption of mTORC2 function alters normal epidermal formation. Ric EKO mice have an ichthyosis-like phenotype at birth with reduced epidermal thickness and enhanced transepidermal water loss, which is similar to what is observed in human patients.…”

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confidence: 99%

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ResTORing barrier function in the skin

Wang

Kaplan

Yang

2020

Journal of Allergy and Clinical Immunology

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

Abstract: From a the Department of Dermatology, b the Center for Molecular Medicine Cologne (CMMC), and g the Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD),

Cited by 30 publications

References 71 publications

The potential pathways underlying the association of propyl-paraben exposure with aeroallergen sensitization and EASI score using metabolomics analysis

The potential pathways underlying the association of propyl-paraben exposure with aeroallergen sensitization and EASI score using metabolomics analysis

Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

ResTORing barrier function in the skin

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