Regulation of energy homeostasis by the ubiquitin-independent REGγ proteasome.
Regulation of energy homeostasis by the ubiquitin-independent REGγ proteasome.
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不依赖泛素的 REG γ 蛋白酶体对能量稳态的调节
DOI：
10.1038/ncomms12497
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发表时间：
2016-08-11
影响因子：
16.6
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Sun L;Fan G;Shan P;Qiu X;Dong S;Liao L;Yu C;Wang T;Gu X;Li Q;Song X;Cao L;Li X;Cui Y;Zhang S;Wang C
维持能量平衡对于细胞的生存是至关重要的。在这里，我们报道了不依赖于三磷酸腺苷和泛素的Regγ-蛋白酶体系统在能量饥饿期间通过抑制rDNA转录在维持能量平衡和细胞存活中发挥作用，rDNA转录是细胞内主要的能量消耗过程。在机制上，REGγ-蛋白酶体通过靶向rDNA转录激活因子SIRT7在正常条件下进行泛素非依赖性降解来限制细胞rDNA转录和能量消耗。此外，能量饥饿导致AMPK介导的SIRT7磷酸化，以及随后依赖REGγ的SIRT7亚细胞的重新分布和降解，从而进一步减少rDNA转录，从而节省能量来克服细胞死亡。能量匮乏是一种很有前途的癌症治疗策略。我们的报告还显示，REGγ基因敲除显著提高了能量代谢抑制剂在小鼠体内的抗肿瘤活性。我们的结果强调了在饥饿条件下维持能量平衡和细胞存活的泛素非依赖过程的控制机制，表明抑制REGγ-蛋白酶体具有潜在的提供肿瘤饥饿益处的潜力。在能量应激条件下，细胞减少核糖体RNA(RRNA)的转录以维持细胞存活。在这里，作者表明，能量应激诱导依赖AMPK的sirt7的磷酸化，促进其泛素不依赖于Regγ的降解，导致rRNA转录下调和细胞存活。
Maintenance of energy homeostasis is essential for cell survival. Here, we report that the ATP- and ubiquitin-independent REGγ-proteasome system plays a role in maintaining energy homeostasis and cell survival during energy starvation via repressing rDNA transcription, a major intracellular energy-consuming process. Mechanistically, REGγ-proteasome limits cellular rDNA transcription and energy consumption by targeting the rDNA transcription activator SirT7 for ubiquitin-independent degradation under normal conditions. Moreover, energy starvation induces an AMPK-directed SirT7 phosphorylation and subsequent REGγ-dependent SirT7 subcellular redistribution and degradation, thereby further reducing rDNA transcription to save energy to overcome cell death. Energy starvation is a promising strategy for cancer therapy. Our report also shows that REGγ knockdown markedly improves the anti-tumour activity of energy metabolism inhibitors in mice. Our results underscore a control mechanism for an ubiquitin-independent process in maintaining energy homeostasis and cell viability under starvation conditions, suggesting that REGγ-proteasome inhibition has a potential to provide tumour-starving benefits. In conditions of energy stress cells reduce transcription of ribosomal RNA (rRNA) to maintain cell survival. Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.