NF2 signaling pathway plays a pro-apoptotic role in β-adrenergic receptor stimulated cardiac myocyte apoptosis.
NF2 signaling pathway plays a pro-apoptotic role in β-adrenergic receptor stimulated cardiac myocyte apoptosis.
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DOI：
10.1371/journal.pone.0196626
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Singh K
中科院分区：
文献类型：
--
作者：
Dalal S;Connelly B;Singh M;Singh K
β-肾上腺素能受体（β-AR）在体内外均可诱导心肌细胞凋亡。神经纤维蛋白2（NF 2）是ezrin/radixin/moesin（ERM）蛋白家族的成员。翻译后修饰如磷酸化和类小泛素化影响NF 2活性、亚细胞定位和功能。在此，我们检验了β-AR刺激诱导NF 2翻译后修饰，NF 2在β-AR刺激的心肌细胞凋亡中起促凋亡作用的假设。用β-AR激动剂（异丙肾上腺素）处理成年大鼠心室肌细胞（ARVMs）15分钟，可增加NF 2的磷酸化（丝氨酸-518）和SUMO化。免疫共沉淀试验证实了β-AR刺激的NF 2的SUMO化。β-AR刺激增强磷酸化和类小泛素化NF 2的核转位。特异性抑制β1-AR和蛋白激酶A（PKA）可降低β-AR刺激的NF 2翻译后修饰的增加，而抑制β2-AR则无影响。使用毛喉素（FSK）激活腺苷酸环化酶模拟β-AR刺激的作用。使用腺病毒刺激β-AR和表达野生型（WT）-NF 2增加了哺乳动物不育样激酶-1/2（MST 1/2）和是活化蛋白（雅普）（NF 2的下游靶标）的磷酸化。在H9 C2心肌细胞中使用siRNA敲低NF 2降低了β-AR刺激的NF 2和雅普磷酸化的增加。siRNA介导的NF 2敲低降低了β-AR刺激的ARVM凋亡增加，而WT-NF 2的表达诱导了ARVM的凋亡。WT-NF 2的表达刺激线粒体死亡途径，如通过c-Jun N-末端激酶（JNK）的活化以及胞质细胞色素c水平和Bax表达的增加所证明的。β-AR刺激通过β1-AR/PKA/cAMP途径影响NF 2的翻译后修饰，NF 2通过雅普的磷酸化（失活）和线粒体死亡途径参与β-AR刺激的心肌细胞凋亡。
β-adrenergic receptor (β-AR) stimulation induces cardiac myocyte apoptosis in vitro and in vivo. Neurofibromin 2 (NF2) is a member of the ezrin/radixin/moesin (ERM) family of proteins. Post-translational modifications such as phosphorylation and sumoylation affect NF2 activity, subcellular localization and function. Here, we tested the hypothesis that β-AR stimulation induces post-translational modifications of NF2, and NF2 plays a pro-apoptotic role in β-AR-stimulated myocyte apoptosis. Treatment of adult rat ventricular myocytes (ARVMs) with β-AR agonist (isoproterenol) for 15 min increased phosphorylation (serine-518) and sumoylation of NF2. Co-immunoprecipitation assay confirmed β-AR-stimulated sumoylation of NF2. β-AR stimulation enhanced nuclear translocation of phosphorylated and sumoylated NF2. Specific inhibition of β1-AR and protein kinase A (PKA) decreased β-AR-stimulated increase in NF2 post-translational modifications, while inhibition of β2-AR had no effect. Activation of adenylyl cyclase using forskolin (FSK) mimicked the effects of β-AR stimulation. β-AR stimulation and expression of wild-type (WT)-NF2 using adenoviruses increased phosphorylation of mammalian sterile like kinase-1/2 (MST1/2) and yes activated protein (YAP), downstream targets of NF2. Knockdown of NF2 using siRNA in H9C2 cardiomyocytes decreased β-AR-stimulated increase in NF2 and YAP phosphorylation. siRNA-mediated knockdown of NF2 decreased β-AR-stimulated increase in apoptosis, while expression of WT-NF2 induced apoptosis in ARVMs. Expression of WT-NF2 stimulated the mitochondrial death pathway as evidenced by activation of c-Jun N-terminal Kinases (JNKs), and increase in cytosolic cytochrome c levels and Bax expression. β-AR stimulation affects post-translational modifications of NF2 via the involvement β1-AR/PKA/cAMP pathway, and NF2 plays a pro-apoptotic role in β-AR-stimulated myocyte apoptosis via the phosphorylation (inactivation) of YAP and involvement of mitochondrial death pathway.
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