Physiological levels of ATP negatively regulate proteasome function.
Physiological levels of ATP negatively regulate proteasome function.
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ATP 的生理水平负向调节蛋白酶体功能
作者：
泛素-蛋白酶体系统的细胞内蛋白降解是ATP依赖性的，体外激活蛋白酶体功能的最佳ATP浓度为~100 μM。细胞内ATP水平通常在低毫摩尔范围内，但在该范围内的水平的ATP显示出抑制体外蛋白酶体肽酶活性。在这里，我们报告了新的证据，支持一个假设，即细胞内ATP在生理水平双向调节26 S蛋白酶体的蛋白水解功能的细胞。首先，我们证实了ATP在体外对26 S蛋白酶体具有双向调节作用，最佳ATP浓度（50-100 μM）刺激蛋白酶体糜蛋白酶样活性。其次，我们发现，操纵细胞内ATP水平也导致培养细胞中蛋白酶体特异性蛋白底物水平的双向变化。最后，增加细胞内ATP的措施增强了蛋白酶体抑制诱导细胞死亡的能力，而减少细胞内ATP则减弱了蛋白酶体抑制诱导细胞死亡的能力。这些数据有力地表明，生理浓度范围内的内源性ATP可以对蛋白酶体活性产生负面影响，从而允许细胞在应激条件下ATP减少时快速上调蛋白酶体活性。
Intracellular protein degradation by the ubiquitin-proteasome system is ATP-dependent and the optimal ATP concentration to activate proteasome function in vitro is ~100 μM. Intracellular ATP levels are generally in the low millimolar range but ATP at a level within this range was shown to inhibit proteasome peptidase activities in vitro. Here we report new evidence that supports a hypothesis that intracellular ATP at the physiological levels bidirectionally regulates 26S proteasome proteolytic function in the cell. First, we confirmed that ATP exerted bidirectional regulation on the 26S proteasome in vitro, with the optimal ATP concentration (between 50–100 μM) stimulating proteasome chymotrypsin-like activities. Second, we found that manipulating intracellular ATP levels also led to bidirectional changes in the levels of proteasome-specific protein substrates in cultured cells. Finally, measures to increase intracellular ATP enhanced, while decreasing intracellular ATP attenuated, the ability of proteasome inhibition to induce cell death. These data strongly suggest that endogenous ATP within the physiological concentration range can exert a negative impact on proteasome activities, allowing the cell to rapidly up-regulate proteasome activity upon ATP reduction under stress conditions.
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DOI：
10.1152/ajpheart.01052.2008
发表时间：
2008-12-01
影响因子：
4.8
作者：
Liu, Jinbao;Zheng, Hanqiao;Wang, Xuejun
通讯作者：
Wang, Xuejun
影响因子：
8.8
作者：
Mikura, Mayumi;Yamaoka, Ippei;Nikawa, Takeshi
通讯作者：
Nikawa, Takeshi
影响因子：
4.8
作者：
Kumarapeli, ARK;Horak, KM;Wang, XJ
通讯作者：
Wang, XJ
DOI：
10.1016/s0022-2828(84)80039-5
发表时间：
1984-01-01
影响因子：
5
作者：
HUMPHREY, SM;HOLLISS, DG;SEELYE, RN
通讯作者：
SEELYE, RN
DOI：
10.1084/jem.191.11.1975
发表时间：
2000-06-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Latta M;Künstle G;Leist M;Wendel A
通讯作者：
Wendel A