PP2A Mediated AMPK Inhibition Promotes HSP70 Expression in Heat Shock Response
PP2A Mediated AMPK Inhibition Promotes HSP70 Expression in Heat Shock Response
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DOI：
10.1371/journal.pone.0013096
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发表时间：
2010-10
期刊：
影响因子：
3.7
通讯作者：
Ting Wang;Qiujing Yu;Juan Chen;Bo Deng;Lihua Qian;Y. Le
中科院分区：
文献类型：
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作者：
Ting Wang;Qiujing Yu;Juan Chen;Bo Deng;Lihua Qian;Y. Le
背景在应激条件下，腺苷酸活化蛋白激酶（AMPK）在能量平衡中起着重要作用，热休克反应是细胞存活的保护机制。AMPK活性与热休克蛋白（HSP）表达的关系在应激下尚不清楚。方法/主要发现我们发现热应激可诱导人和啮齿类动物多种细胞中AMPKα亚基（AMPKα）的去磷酸化。在HepG 2细胞中，AMPKα在热应激下的去磷酸化反过来引起AMPK的两个下游靶点乙酰辅酶A羧化酶的去磷酸化和磷酸烯醇式丙酮酸羧激酶的上调，证实了热应激对AMPK活性的抑制。用磷酸酶2A（PP 2A）抑制剂冈田酸处理HepG 2细胞或通过RNA干扰抑制PP 2A表达可有效逆转热应激诱导的AMPKα去磷酸化，表明热应激通过激活PP 2A抑制AMPK。AMPK特异性激活剂AICAR可抑制热应激和其他HSP诱导剂（CdCl 2、雷公藤红素、MG 132）诱导的HSP 70表达。RNA干扰抑制AMPKα表达可逆转AICAR对热应激下HSP 70表达的抑制作用。这些结果表明，在应激下AMPK抑制有助于HSP 70表达。机制研究表明，AICAR激活AMPK对热应激诱导的HSF 1核转位、磷酸化以及与HSP 70基因启动子区热反应元件的结合没有影响，但显着降低HSP 70 mRNA的稳定性。这些结果表明，在热休克反应，PP 2A介导的AMPK抑制上调HSP 70的表达至少部分通过稳定其mRNA，这表明一个新的机制，应激诱导HSP。
Background Under stress, AMP-activated protein kinase (AMPK) plays a central role in energy balance, and the heat shock response is a protective mechanism for cell survival. The relationship between AMPK activity and heat shock protein (HSP) expression under stress is unclear. Methodology/Principal Findings We found that heat stress induced dephosphorylation of AMPKα subunit (AMPKα) in various cell types from human and rodent. In HepG2 cells, the dephosphorylation of AMPKα under heat stress in turn caused dephosphorylation of acetyl-CoA carboxylase and upregulation of phosphoenolpyruvate carboxykinase, two downstream targets of AMPK, confirming the inhibition of AMPK activity by heat stress. Treatment of HepG2 cells with phosphatase 2A (PP2A) inhibitor okadaic acid or inhibition of PP2A expression by RNA interference efficiently reversed heat stress-induced AMPKα dephosphorylation, suggesting that heat stress inhibited AMPK through activation of PP2A. Heat stress- and other HSP inducer (CdCl2, celastrol, MG132)-induced HSP70 expression could be inhibited by AICAR, an AMPK specific activator. Inhibition of AMPKα expression by RNA interference reversed the inhibitory effect of AICAR on HSP70 expression under heat stress. These results indicate that AMPK inhibition under stress contribute to HSP70 expression. Mechanistic studies showed that activation of AMPK by AICAR had no effect on heat stress-induced HSF1 nuclear translocation, phosphorylation and binding with heat response element in the promoter region of HSP70 gene, but significantly decreased HSP70 mRNA stability. Conclusions/Significance These results demonstrate that during heat shock response, PP2A mediated AMPK inhibition upregulates HSP70 expression at least partially through stabilizing its mRNA, which suggests a novel mechanism for HSP induction under stress.