Physiological levels of ATP negatively regulate proteasome function  

作　　者：Hongbiao Huang Xiaoyan Zhang Shujue Li Ningning Liu Wen Elan Emily McDowell Ping Zhou Canguo Zhao Haiping Guo Change Zhang Changshan Yang Guangmei Wen Xiaoxian Dong Li Lu Ningfang Ma Weihua Dong Q Ping Dou Xuejun Wang Jinbao Liu 

机构地区：[1]Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical College, Guangzhou, Guangdong 510182, China [2]Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA [3]The Prevention Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA [4]Department of Pathology, School of Medicine, Wayne State University, Detroit, M148201, USA

出　　处：《Cell Research》2010年第12期1372-1385,共14页细胞研究（英文版）

基　　金：Acknowledgments This work was supported by the National High Technol- ogy Research and Development Program of China （Project 2006AA02Z4B5）, the National Natural Science Foundation of China （Project 2010）, and a Key Project （9251018201002） of Guangdong Province Natural Science Foundation （to JL）. It was also supported in part by Grants HL072166, HL085629, and HL068936 of the NIH and an Established Investigator Award （0740025N） of the American Heart Association （to XW）.

摘　　要：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. IntraceUular 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 100μM） 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 intraceHular 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.

关 键 词：ATP PROTEASOME REGULATION APOPTOSIS 

分 类 号：Q511[生物学—生物化学] S661.1[农业科学—果树学]