Volume 20, No 12, Dec 2010

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 20 Issue 12, December 2010: 1372-1385

ORIGINAL ARTICLES

Physiological levels of ATP negatively regulate proteasome function

Hongbiao Huang^1,*, Xiaoyan Zhang^1,*, Shujue Li^1,*, Ningning Liu^1,*, Wen Lian^1,*, Emily McDowell², Ping Zhou¹, Canguo Zhao¹, Haiping Guo¹, Change Zhang¹, Changshan Yang¹, Guangmei Wen¹, Xiaoxian Dong¹, Li Lu¹, Ningfang Ma¹, Weihua Dong¹, Q. Ping Dou^1,3,4, Xuejun Wang^1,2 and Jinbao Liu¹

¹Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical College, Guangzhou, Guangdong 510182, China

²Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA

³The Prevention Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA

⁴Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA Correspondence: Jinbao Liu, Xuejun Wang,(liujinbao1@yahoo.com.cn; xuejun.wang@usd.edu)

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 and 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 upregulate proteasome activity on ATP reduction under stress conditions.

Cell Research (2010) 20:1372-1385. doi:10.1038/cr.2010.123; published online 31 August 2010

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