A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis.
A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis.
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DOI：
10.1016/j.jaci.2016.09.052
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
O'Shaughnessy RF
中科院分区：
文献类型：
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作者：
Naeem AS;Tommasi C;Cole C;Brown SJ;Zhu Y;Way B;Willis Owen SA;Moffatt M;Cookson WO;Harper JI;Di WL;Brown SJ;Reinheckel T;O'Shaughnessy RF
由聚丝蛋白基因（FLG）编码的聚丝蛋白是皮肤对外界环境屏障的重要组成部分，FLG的遗传缺陷与特应性皮炎（AD）密切相关。然而，并非所有AD患者都有FLG突变。我们假设这些患者可能在丝聚蛋白表达和加工中存在其他缺陷，导致屏障破坏和AD，因此我们提出了这种疾病的新治疗靶点。我们描述了MTOR复合物1（RAPTOR）的雷帕霉素复合物1/2蛋白亚基调节相关蛋白的机制靶点，丝氨酸/苏氨酸激酶V-Akt小鼠胸腺瘤病毒癌基因同源物1（AKT 1）和蛋白酶组织蛋白酶H（CTSH）之间的关系，我们建立了在聚丝蛋白表达和加工中的作用。AD患者RAPTOR水平升高与聚丝蛋白表达降低相关。在角质形成细胞培养物中，RAPTOR上调或AKT 1短发夹RNA敲低降低蛋白酶CTSH的表达。CTSH缺陷小鼠和CTSH短发夹RNA敲低角质形成细胞的皮肤显示聚丝蛋白加工减少，并且小鼠具有受损的皮肤屏障功能和轻度促炎表型。我们的研究结果强调了一种新的和潜在的可治疗的信号轴控制聚丝蛋白的表达和加工，是有缺陷的AD患者。
Filaggrin, which is encoded by the filaggrin gene (FLG), is an important component of the skin's barrier to the external environment, and genetic defects in FLG strongly associate with atopic dermatitis (AD). However, not all patients with AD have FLG mutations. We hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and therefore we present novel therapeutic targets for this disease. We describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in patients with AD. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype. Our findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.