iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death
iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death
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DOI：
10.1073/pnas.1408111112
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发表时间：
2015-03-03
影响因子：
11.1
通讯作者：
Lu, Xin
中科院分区：
文献类型：
--
作者：
Notari, Mario;Hu, Ying;Lu, Xin
桥粒是存在于承受物理应力的细胞（如心肌细胞）中的锚定连接。在人类患者和动物模型中发现的桥粒组分的频繁突变强调了桥粒在维持心肌稳态中的重要性。致心律失常性右心室心肌病（ARVC）是由桥粒组分突变引起的表型，约有50%的患者发生，然而，其余50%的患者的原因仍然未知。p53抑制蛋白（inhibitor of apoptosis-stimulating protein of p53，iASPP）是一种进化上保守的p53抑制蛋白，近年来发现，iASPP基因的自发突变导致无角赫里福德犊牛和Wa 3小鼠常染色体隐性心肌病的发生。然而，介导iASPP这种假定功能的分子机制是完全未知的。在这里，我们表明，iASPP在人类和小鼠有丝分裂后心肌细胞的闰盘表达。iASPP与心肌细胞中的桥粒斑蛋白和结蛋白相互作用，以在体外和体内维持桥粒和中间丝网络的完整性。iASPP缺陷特异性诱导胚胎16.5天的小鼠胚胎右心室扩张。具有外显子8缺失的iASPP缺陷小鼠（Ppp 1 r13 l（Delta 8/Delta 8））死于心脏性猝死，显示ARVC的特征。来自六个人ARVC病例中的四个的心肌细胞中的夹层盘显示iASPP减少或丢失。ARVC衍生的桥粒斑蛋白突变体DSP-1-V30 M和DSP-1-S299 R表现出较弱的与iASPP的结合。这些数据表明，通过与桥斑蛋白和结蛋白相互作用，iASPP是体外和体内桥粒功能的重要调节剂。这种新发现的iASPP特性可能为ARVC的发病机制提供新的分子见解。
Desmosomes are anchoring junctions that exist in cells that endure physical stress such as cardiac myocytes. The importance of desmosomes in maintaining the homeostasis of the myocardium is underscored by frequent mutations of desmosome components found in human patients and animal models. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a phenotype caused by mutations in desmosomal components in similar to 50% of patients, however, the causes in the remaining 50% of patients still remain unknown. A deficiency of inhibitor of apoptosis-stimulating protein of p53 (iASPP), an evolutionarily conserved inhibitor of p53, caused by spontaneous mutation recently has been associated with a lethal autosomal recessive cardiomyopathy in Poll Hereford calves and Wa3 mice. However, the molecular mechanisms that mediate this putative function of iASPP are completely unknown. Here, we show that iASPP is expressed at intercalated discs in human and mouse postmitotic cardiomyocytes. iASPP interacts with desmoplakin and desmin in cardiomyocytes to maintain the integrity of desmosomes and intermediate filament networks in vitro and in vivo. iASPP deficiency specifically induces right ventricular dilatation in mouse embryos at embryonic day 16.5. iASPP-deficient mice with exon 8 deletion (Ppp1r13l(Delta 8/Delta 8)) die of sudden cardiac death, displaying features of ARVC. Intercalated discs in cardiomyocytes from four of six human ARVC cases show reduced or loss of iASPP. ARVC-derived desmoplakin mutants DSP-1-V30M and DSP-1-S299R exhibit weaker binding to iASPP. These data demonstrate that by interacting with desmoplakin and desmin, iASPP is an important regulator of desmosomal function both in vitro and in vivo. This newly identified property of iASPP may provide new molecular insight into the pathogenesis of ARVC.