Department of Dermatology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Department of Dermatology, University of Cologne, Cologne, Germany.
J Allergy Clin Immunol. 2020 Jan;145(1):283-300.e8. doi: 10.1016/j.jaci.2019.07.033. Epub 2019 Aug 8.
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.
Here we highlight a specific role of mammalian target of rapamycin complex 2 (mTORC2) signaling in epidermal barrier formation.
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] mice). Epidermal structure and barrier function were investigated through a combination of gene expression, biochemical, morphological and functional analysis in Ric and control mice.
Ric 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 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.
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.
表皮屏障形成的干扰会严重损害整体皮肤功能，导致皮肤出现干燥、鳞屑、鱼鳞样外观，这是多种皮肤疾病的特征，包括鱼鳞病、特应性皮炎和多种临床湿疹变体。协调控制表皮屏障形成和稳态的多种因素的总体分子机制仍有待阐明。
本文强调了哺乳动物雷帕霉素靶蛋白复合物 2（mTORC2）信号在表皮屏障形成中的特定作用。
通过在小鼠表皮中特异性敲除雷帕霉素不敏感的 mTORC2 复合物的伴侣 rapamycin-insensitive companion of target of rapamycin（Rictor，编码 mTORC2 的必需亚基）（表皮特异性同源重组 Ric 小鼠），特异性破坏表皮 mTORC2 信号。通过 Ric 和对照小鼠的基因表达、生化、形态和功能分析相结合，研究了表皮结构和屏障功能。
Ric 新生小鼠表现出鱼鳞样表型，特征为表皮从头脂质合成失调、脂质层结构改变以及丝聚蛋白（FLG）加工异常。尽管存在转录表皮修复反应的代偿，但 Ric 小鼠的保护性表皮功能受损，表现为经皮水分丢失增加、角朊细胞脆性增加、树突状表皮 T 细胞减少以及经皮免疫反应过度。通过表达组成型 Akt，挽救 mTORC2 缺陷角质形成细胞中的 Akt-Ser473 磷酸化，恢复了 FLG 加工。
我们的发现揭示了屏障形成中的关键代谢信号转导，其中表皮 mTORC2 活性在角蛋白细胞分化过程中控制 FLG 加工和从头表皮脂质合成。我们的研究结果为表皮屏障形成提供了新的机制见解，并为恢复有缺陷的表皮屏障条件开辟了新的治疗机会。
