Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
Department of Medicine, University of Alberta, Edmonton, Alberta, T6G 2B7, Canada.
Cell Death Differ. 2018 Jul;25(7):1289-1303. doi: 10.1038/s41418-017-0039-6. Epub 2018 Jan 19.
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.
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，炎症增强是这些疾病的共同特征。先前的研究表明，凋亡刺激 p53 蛋白抑制剂（iASPP）在细胞-细胞连接处调节桥粒的完整性，并在核内进行转录，其缺失会导致小鼠、牛和人类出现心皮疾病。由于 iASPP 是一种具有多种功能的广泛表达的穿梭蛋白，一个关键问题是观察到的心皮表型是否是由 iASPP 在心肌细胞和角质细胞中的自主作用缺失引起的，还是由免疫细胞等其他细胞类型中 iASPP 的缺失引起的。为了解决这个问题，我们开发了心肌细胞特异性和角质细胞特异性 iASPP 缺陷型小鼠模型，并表明心肌细胞或角质细胞中 iASPP 的细胞类型特异性缺失足以分别诱导心脏或皮肤疾病。此外，角质细胞特异性 iASPP 缺陷型小鼠的眼睑发育和伤口愈合延迟。在角质细胞中，连接的 iASPP 对于稳定桥粒至关重要，iASPP 缺失会导致细胞迁移增加和紊乱，以及细胞黏附受损，这与伤口愈合延迟一致。iASPP 缺陷导致心皮综合征、眼睑发育不良和伤口愈合受损的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和皮肤疾病。
