Physiological levels of ATP negatively regulate proteasome function.
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.
Huang
Hongbiao
H
Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical College, Guangzhou, Guangdong 510182, China.
Zhang
Xiaoyan
X
Li
Shujue
S
Liu
Ningning
N
Lian
Wen
W
McDowell
Emily
E
Zhou
Ping
P
Zhao
Canguo
C
Guo
Haiping
H
Zhang
Change
C
Yang
Changshan
C
Wen
Guangmei
G
Dong
Xiaoxian
X
Lu
Li
L
Ma
Ningfang
N
Dong
Weihua
W
Dou
Q Ping
QP
Wang
Xuejun
X
Liu
Jinbao
J
D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000502:physiology; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009840:Oligomycins / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism
D001897:Boronic Acids; D007976:Leupeptins; C423917:MG 262; D009840:Oligomycins; D025801:Ubiquitin; D000255:Adenosine Triphosphate; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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