Abstract
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.
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Acknowledgements
This work was supported by the National High Technology 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).
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Huang, H., Zhang, X., Li, S. et al. Physiological levels of ATP negatively regulate proteasome function. Cell Res 20, 1372–1385 (2010). https://doi.org/10.1038/cr.2010.123
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DOI: https://doi.org/10.1038/cr.2010.123
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