Cell autonomous role of iASPP deficiency in causing cardiocutaneous disorders
Cell autonomous role of iASPP deficiency in causing cardiocutaneous disorders
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DOI：
10.1038/s41418-017-0039-6
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发表时间：
2018-07-01
影响因子：
12.4
通讯作者：
Lu, Xin
中科院分区：
文献类型：
--
作者：
Dedeic, Zinaida;Sutendra, Gopinath;Lu, Xin
桥粒成分在动物和人类的心脏和皮肤疾病中经常发生突变，并且炎症增强是这些疾病的共同特征。先前的研究表明，细胞凋亡刺激 p53 蛋白 (iASPP) 抑制剂可调节细胞-细胞连接处的桥粒完整性和细胞核中的转录，其缺陷会导致小鼠、牛和人类的心血管疾病。由于 iASPP 是一种普遍表达的具有多种功能的穿梭蛋白，因此一个关键问题是观察到的心脏皮肤表型是否是由于 iASPP 在心肌细胞和角质形成细胞中的细胞自主作用丧失引起的，或者是由于其他细胞类型（如免疫细胞）中 iASPP 的丧失引起的。为了解决这个问题，我们开发了心肌细胞特异性和角质形成细胞特异性 iASPP 缺陷小鼠模型，并表明心肌细胞或角质形成细胞中 iASPP 的细胞类型特异性缺失足以分别诱发心脏或皮肤疾病。此外，角质形成细胞特异性 iASPP 缺陷小鼠会延迟眼睑发育和伤口愈合。在角质形成细胞中，连接 iASPP 对于稳定桥粒至关重要，iASPP 缺陷会导致细胞迁移增加和紊乱，以及细胞粘附受损，这与伤口愈合延迟一致。 iASPP 缺陷在引起心源性皮肤综合征、眼睑发育受损和伤口愈合方面的细胞自主作用的鉴定表明，iASPP 基因的变异也可能导致多基因心脏病和皮肤病。
Desmosome components are frequently mutated in cardiac and cutaneous disorders in animals and humans and enhanced inflammation is a common feature of these diseases. Previous studies showed that inhibitor of Apoptosis Stimulating p53 Protein (iASPP) regulates desmosome integrity at cell-cell junctions and transcription in the nucleus, and its deficiency causes cardiocutaneous disorder in mice, cattle, and humans. As iASPP is a ubiquitously expressed shuttling protein with multiple functions, a key question is whether the observed cardiocutaneous phenotypes are caused by loss of a cell autonomous role of iASPP in cardiomyocytes and keratinocytes specifically or by a loss of iASPP in other cell types such as immune cells. To address this, we developed cardiomyocyte-specific and keratinocyte-specific iASPP-deficient mouse models and show that the cell-type specific loss of iASPP in cardiomyocytes or keratinocytes is sufficient to induce cardiac or cutaneous disorders, respectively. Additionally, keratinocyte-specific iASPP-deficient mice have delayed eyelid development and wound healing. In keratinocytes, junctional iASPP is critical for stabilizing desmosomes and iASPP deficiency results in increased and disorganized cell migration, as well as impaired cell adhesion, consistent with delayed wound healing. The identification of a cell autonomous role of iASPP deficiency in causing cardiocutaneous syndrome, impaired eyelid development and wound healing suggests that variants in the iASPP gene also may contribute to polygenic heart and skin diseases.