Novel Cardiac Apoptotic Pathway The Dephosphorylation of Apoptosis Repressor With Caspase Recruitment Domain by Calcineurin
Novel Cardiac Apoptotic Pathway The Dephosphorylation of Apoptosis Repressor With Caspase Recruitment Domain by Calcineurin
复制标题
新型心脏凋亡途径钙调神经磷酸酶对具有 Caspase 募集结构域的凋亡阻遏蛋白进行去磷酸化
DOI：
10.1161/circulationaha.107.750869
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发表时间：
2008-11-25
期刊：
影响因子：
37.8
通讯作者：
Li, Pei-Feng
中科院分区：
文献类型：
--
作者：
Tan, Wei-Qi;Wang, Jian-Xun;Li, Pei-Feng
背景-具有半胱天冬酶募集结构域 (ARC) 的凋亡阻遏蛋白在心肌细胞中大量表达。蛋白激酶CK2可以磷酸化ARC的苏氨酸149位点，从而使ARC能够拮抗细胞凋亡。 ARC 磷酸化以组成型方式发生。尽管如此，心肌细胞仍然会发生与心肌梗塞和心力衰竭等心脏病相关的细胞凋亡。细胞凋亡的发生是否与病理条件下ARC保护作用的丧失有关尚不清楚。方法和结果-用异丙肾上腺素或醛固酮处理的心肌细胞中ARC磷酸化水平降低。我们探索了 ARC 磷酸化水平降低的分子机制。我们的结果表明，直接孵育或与钙调神经磷酸酶共表达都会导致 ARC 磷酸化水平降低。抑制钙调神经磷酸酶可以减弱异丙肾上腺素或醛固酮治疗时 ARC 磷酸化水平的降低。这些数据表明ARC磷酸化水平的降低与其被钙调神经磷酸酶去磷酸化有关。我们的结果进一步表明，ARC可以阻止异丙肾上腺素和醛固酮诱导的细胞凋亡，但这种功能取决于其磷酸化状态。异丙肾上腺素和醛固酮上调Fas配体表达，异丙肾上腺素和醛固酮诱导细胞凋亡需要Fas配体和caspase-8。然而，磷酸化而非去磷酸化的 ARC 能够抑制 caspase-8 介导的细胞凋亡。磷酸化的 ARC 通过直接与 procaspase-8 结合并抑制其与具有死亡结构域的 Fas 相关蛋白的相互作用来发挥其针对 caspase-8 的作用。结论-我们的研究确定了一种新的心脏凋亡途径，其中 ARC 被钙调神经磷酸酶去磷酸化。该途径可能是心脏细胞凋亡机制的一个组成部分。 （流通。2008 年；118：2268-2276。）
Background-Apoptosis repressor with caspase recruitment domain (ARC) is abundantly expressed in cardiomyocytes. Protein kinase CK2 can phosphorylate ARC at threonine-149, thereby enabling ARC to antagonize apoptosis. ARC phosphorylation occurs in a constitutive manner. Nevertheless, cardiomyocytes still undergo apoptosis that is related to cardiac diseases such as myocardial infarction and heart failure. Whether the occurrence of apoptosis is related to the loss of protection by ARC under pathological conditions remains unknown.Methods and Results-ARC phosphorylation levels are decreased in cardiomyocytes treated with isoproterenol or aldosterone. We explored the molecular mechanism by which ARC phosphorylation levels are decreased. Our results reveal that either direct incubation or coexpression with calcineurin leads to a decrease in ARC phosphorylation levels. Inhibition of calcineurin can attenuate the reduction in ARC phosphorylation levels on treatment with isoproterenol or aldosterone. These data indicate that the reduction in ARC phosphorylation levels is related to its dephosphorylation by calcineurin. Our results further reveal that ARC can prevent isoproterenol-and aldosterone-induced apoptosis, but this function depends on its phosphorylation status. Isoproterenol and aldosterone upregulate Fas ligand expression, and Fas ligand and caspase-8 are required for isoproterenol and aldosterone to induce apoptosis. However, phosphorylated but not dephosphorylated ARC is able to inhibit caspase-8-mediated apoptosis. Phosphorylated ARC exerts its effects against caspase-8 by directly associating with procaspase-8 and inhibiting its interaction with Fas-associated protein with death domain.Conclusions-Our study identifies a novel cardiac apoptotic pathway in which ARC is dephosphorylated by calcineurin. This pathway could be a component in the cardiac apoptotic machinery. (Circulation. 2008; 118: 2268-2276.)