Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation
Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation
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DOI：
10.1016/j.jaci.2019.07.033
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发表时间：
2020-01-01
影响因子：
14.2
通讯作者：
Eming, Sabine A.
中科院分区：
文献类型：
--
作者：
Ding, Xiaolei;Willenborg, Sebastian;Eming, Sabine A.
背景资料：表皮屏障形成的扰动将严重损害整体皮肤功能，导致干燥和鳞状、鱼鳞病样皮肤表型，其是广泛的皮肤疾病的标志，包括鱼鳞病、特应性皮炎和多种临床湿疹变体。一个总体的分子机制，协调控制表皮屏障形成和稳态的众多因素仍有待阐明。目的：在这里，我们强调了雷帕霉素复合物2（mTORC 2）的哺乳动物靶信号在表皮屏障形成的特定作用。方法：通过删除雷帕霉素靶点的雷帕霉素不敏感伴侣（Rictor）特异性破坏表皮mTORC 2信号传导，编码小鼠表皮中mTORC 2的必需亚基（表皮特异性纯合Rictor缺失[Ric（EKO）]小鼠）。结果：Ric（EKO）新生小鼠表现出鱼鳞病样表型，其特征为表皮脂质合成失调、脂质层结构改变和微丝聚集蛋白（FLG）加工异常。尽管有代偿性的转录表皮修复反应，Ric（EKO）小鼠的保护性表皮功能受损，如经皮失水增加、角质细胞脆性增强、树突状表皮T细胞减少和过度的经皮免疫反应所示。恢复Akt-Ser 473磷酸化mTORC 2缺陷角质形成细胞通过表达组成性Akt拯救FLG processing.Conclusion：我们的研究结果揭示了一个关键的代谢信号传递屏障的形成，其中表皮mTORC 2活性控制FLG加工和从头表皮脂质合成在角质化。我们的研究结果为表皮屏障形成提供了新的机制见解，并可能为修复有缺陷的表皮屏障状况开辟新的治疗机会。
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.