Glyceraldehyde-3-phosphate dehydrogenase interacts with proapoptotic kinase mst1 to promote cardiomyocyte apoptosis.
Glyceraldehyde-3-phosphate dehydrogenase interacts with proapoptotic kinase mst1 to promote cardiomyocyte apoptosis.
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3-磷酸甘油醛脱氢酶与促凋亡激酶 Mst1 相互作用促进心肌细胞凋亡
DOI：
10.1371/journal.pone.0058697
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sun J
中科院分区：
文献类型：
--
作者：
You B;Huang S;Qin Q;Yi B;Yuan Y;Xu Z;Sun J
哺乳动物不育20-样蛋白1(Mst1)是河马信号通路的重要组成部分，它调控哺乳动物细胞接触抑制、器官大小控制、细胞凋亡和肿瘤抑制等多种生物学过程。MST1的激活导致心肌细胞凋亡和扩张性心肌病，在心脏疾病中起着重要作用。然而，心脏中Mst1激活的机制仍不清楚。在以Mst1为诱饵的人心脏cDNA文库酵母双杂交筛选中，3-磷酸甘油醛脱氢酶(GAPDH)被鉴定为与Mst1相互作用的蛋白。在共转染的HEK293细胞和小鼠心脏匀浆中，免疫共沉淀法证实了GAPDH与Mst1的相互作用，其中GAPDH与Mst1的激酶结构域相互作用，而GAPDH的C端催化结构域介导其与Mst1的相互作用。此外，Mst1与GAPDH的相互作用导致了GAPDH的强烈磷酸化，并显著增加了细胞中Mst1的活性。白屈菜红碱是一种有效的细胞凋亡诱导剂，它显著增加了心肌细胞中GAPDH和Mst1的核转位和相互作用。GAPDH的过表达显著增加Mst1介导的细胞凋亡，而GAPDH的敲除显著减弱白屈菜红碱或缺氧/复氧诱导的Mst1激活和心肌细胞的凋亡。这些发现揭示了GAPDH在Mst1激活和心肌细胞凋亡中的新功能，并提示GAPDH与Mst1相互作用的中断可能预防与细胞凋亡相关的心脏疾病，如心力衰竭和缺血性心脏病。
Mammalian sterile 20-like kinase 1 (Mst1) is a critical component of the Hippo signaling pathway, which regulates a variety of biological processes ranging from cell contact inhibition, organ size control, apoptosis and tumor suppression in mammals. Mst1 plays essential roles in the heart disease since its activation causes cardiomyocyte apoptosis and dilated cardiomyopathy. However, the mechanism underlying Mst1 activation in the heart remains unknown. In a yeast two-hybrid screen of a human heart cDNA library with Mst1 as bait, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified as an Mst1-interacting protein. The interaction of GAPDH with Mst1 was confirmed by co-immunoprecipitation in both co-transfected HEK293 cells and mouse heart homogenates, in which GAPDH interacted with the kinase domain of Mst1, whereas the C-terminal catalytic domain of GAPDH mediated its interaction with Mst1. Moreover, interaction of Mst1 with GAPDH caused a robust phosphorylation of GAPDH and markedly increased the Mst1 activity in cells. Chelerythrine, a potent inducer of apoptosis, substantially increased the nuclear translocation and interaction of GAPDH and Mst1 in cardiomyocytes. Overexpression of GAPDH significantly augmented the Mst1 mediated apoptosis, whereas knockdown of GAPDH markedly attenuated the Mst1 activation and cardiomyocyte apoptosis in response to either chelerythrine or hypoxia/reoxygenation. These findings reveal a novel function of GAPDH in Mst1 activation and cardiomyocyte apoptosis and suggest that disruption of GAPDH interaction with Mst1 may prevent apoptosis related heart diseases such as heart failure and ischemic heart disease.
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影响因子：
4.8
作者：
Creasy, CL;Ambrose, DM;Chernoff, J
通讯作者：
Chernoff, J
影响因子：
21.3
作者：
Sen, Nilkantha;Hara, Makoto R.;Sawa, Akira
通讯作者：
Sawa, Akira
影响因子：
20.1
作者：
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通讯作者：
Sadoshima J
DOI：
10.1006/bbrc.2000.3246
发表时间：
2000-08-28
影响因子：
3.1
作者：
Nagy, E;Henics, T;Kellermayer, M
通讯作者：
Kellermayer, M
影响因子：
8
作者：
Chan, EH;Nousiainen, M;Silljé, HHW
通讯作者：
Silljé, HHW