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Activation of γ2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion InjuryNovelty and Significance
Circulation Research ( IF 20.1 ) Pub Date : 2017-10-27 , DOI: 10.1161/circresaha.117.311159
Yang Cao 1 , Naveen Bojjireddy 1 , Maengjo Kim 1 , Tao Li 1 , Peiyong Zhai 1 , Narayani Nagarajan 1 , Junichi Sadoshima 1 , Richard D. Palmiter 1 , Rong Tian 1
Affiliation  

Rationale: AMPK (AMP-activated protein kinase) is a heterotrimeric protein that plays an important role in energy homeostasis and cardioprotection. Two isoforms of each subunit are expressed in the heart, but the isoform-specific function of AMPK remains unclear.
Objective: We sought to determine the role of γ2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the γ-subunit in the heart.
Methods and Results: We found that γ2 but not γ1 or γ3 subunit translocated into nucleus on AMPK activation. Nuclear accumulation of AMPK complexes containing γ2-subunit phosphorylated and inactivated RNA Pol I (polymerase I)–associated transcription factor TIF-IA at Ser-635, precluding the assembly of transcription initiation complexes for rDNA. The subsequent downregulation of pre-rRNA level led to attenuated endoplasmic reticulum (ER) stress and cell death. Deleting γ2-AMPK led to increases in pre-rRNA level, ER stress markers, and cell death during glucose deprivation, which could be rescued by inhibition of rRNA processing or ER stress. To study the function of γ2-AMPK in the heart, we generated a mouse model with cardiac-specific deletion of γ2-AMPK (cardiac knockout [cKO]). Although the total AMPK activity was unaltered in cKO hearts because of upregulation of γ1-AMPK, the lack of γ2-AMPK sensitizes the heart to myocardial ischemia/reperfusion injury. The cKO failed to suppress pre-rRNA level during ischemia/reperfusion and showed a greater infarct size. Conversely, cardiac-specific overexpression of γ2-AMPK decreased ribosome biosynthesis and ER stress during ischemia/reperfusion insult, and the infarct size was reduced.
Conclusions: The γ2-AMPK translocates into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, thus ameliorating ER stress and cell death. Increased γ2-AMPK activity is required to protect against ischemia/reperfusion injury. Our study reveals an isoform-specific function of γ2-AMPK in modulating ribosome biosynthesis, cell survival, and cardioprotection.


中文翻译:

γ2-AMPK的激活抑制核糖体的生物发生,并保护其免受心肌缺血/再灌注损伤的新颖性和意义

原理: AMPK(AMP激活的蛋白激酶)是一种异三聚体蛋白,在能量稳态和心脏保护中起着重要作用。每个亚基的两个同工型在心脏中表达,但AMPK的同工型特异性功能仍不清楚。
目的:我们试图使用生物工程细胞系和小鼠模型来确定γ2-AMPK在心脏应激反应中的作用,所述小鼠模型包含心脏中γ-亚基的任一同工型。
方法和结果:我们发现,在AMPK激活时,γ2但不是γ1或γ3亚基转移到细胞核中。包含γ2-亚基磷酸化和失活的RNA Pol I(聚合酶I)相关转录因子TIF-IA的AMPK复合物在Ser-635处的核积累,不包括rDNA转录起始复合物的组装。随后的前rRNA水平下调导致内质网(ER)应激减弱和细胞死亡。删除γ2-AMPK会导致前rRNA水平升高,内质网应激指标和葡萄糖剥夺过程中细胞死亡的增加,这可以通过抑制rRNA加工或内质网应激来挽救。为了研究γ2-AMPK在心脏中的功能,我们建立了具有心脏特异性γ2-AMPK缺失(心脏敲除[cKO])的小鼠模型。尽管由于γ1-AMPK的上调,cKO心脏中的总AMPK活性没有改变,但缺乏γ2-AMPK会使心脏对心肌缺血/再灌注损伤敏感。在缺血/再灌注期间,cKO无法抑制前rRNA的水平,并显示出更大的梗塞面积。相反,在缺血/再灌注损伤期间,γ2-AMPK的心脏特异性过表达降低了核糖体的生物合成和内质网应激,并缩小了梗塞面积。
结论: γ2-AMPK易位进入细胞核,抑制应激过程中rRNA的前转录和核糖体的生物合成,从而减轻ER应激和细胞死亡。需要增加的γ2-AMPK活性来防止缺血/再灌注损伤。我们的研究揭示了γ2-AMPK在调节核糖体生物合成,细胞存活和心脏保护中的同工型特异性功能。
更新日期:2017-10-27
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