Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease.
Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease.
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DOI：
10.1172/jci.insight.170739
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发表时间：
2023-09-22
期刊：
影响因子：
8
通讯作者：
Simpson, Cory L.
中科院分区：
文献类型：
--
作者：
Zaver, Shivam A.;Sarkar, Mrinal K.;Egolf, Shaun;Zou, Jonathan;Tiwaa, Afua;Capell, Brian C.;Gudjonsson, Johann E.;Simpson, Cory L.
编码肌质内质网钙ATP酶2（SERCA 2）的ATP 2A 2基因突变在20多年前与Darier病有关;然而，对于这种引起复发性皮肤起泡和感染的疾病仍然没有靶向治疗。由于Atp 2a 2基因敲除小鼠不表型其病理，我们建立了一个人类组织模型的Darier病，以阐明其发病机制，并确定潜在的治疗。利用CRISPR/Cas9，我们产生了缺乏SERCA 2的人角质形成细胞，其复制了Darier病的特征，包括细胞间粘附减弱和器官型表皮的分化缺陷。为了鉴定SERCA 2耗竭下游的致病驱动因子，我们进行了RNA测序和蛋白质组学分析。SERCA 2缺陷型角质形成细胞缺乏表皮完整性所需的桥粒和细胞骨架蛋白，并表现出过量的MAPK信号传导，其调节角质形成细胞的粘附和分化。免疫染色患者活检证实了这些发现，病变显示角蛋白缺乏，钙粘蛋白定位错误，ERK过度磷酸化。用MEK抑制剂抑制ERK活性拯救了粘附蛋白表达并恢复了角质形成细胞片层的完整性，尽管SERCA 2耗尽或化学抑制。总之，将多组学分析与作为临床前模型的人类器官型表皮相结合，我们发现SERCA 2单倍不足通过ERK信号传导破坏角质形成细胞中的关键粘附组分，并将MEK抑制确定为Darier病的治疗策略。
Mutation of the ATP2A2 gene encoding sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) was linked to Darier disease more than 2 decades ago; however, there remain no targeted therapies for this disorder causing recurrent skin blistering and infections. Since Atp2a2-knockout mice do not phenocopy its pathology, we established a human tissue model of Darier disease to elucidate its pathogenesis and identify potential therapies. Leveraging CRISPR/Cas9, we generated human keratinocytes lacking SERCA2, which replicated features of Darier disease, including weakened intercellular adhesion and defective differentiation in organotypic epidermis. To identify pathogenic drivers downstream of SERCA2 depletion, we performed RNA sequencing and proteomics analysis. SERCA2-deficient keratinocytes lacked desmosomal and cytoskeletal proteins required for epidermal integrity and exhibited excess MAPK signaling, which modulates keratinocyte adhesion and differentiation. Immunostaining patient biopsies substantiated these findings, with lesions showing keratin deficiency, cadherin mislocalization, and ERK hyperphosphorylation. Dampening ERK activity with MEK inhibitors rescued adhesive protein expression and restored keratinocyte sheet integrity despite SERCA2 depletion or chemical inhibition. In sum, coupling multiomic analysis with human organotypic epidermis as a preclinical model, we found that SERCA2 haploinsufficiency disrupts critical adhesive components in keratinocytes via ERK signaling and identified MEK inhibition as a treatment strategy for Darier disease.
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影响因子：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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作者：
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