SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation.
The physiological function of Sentrin/SUMO-specific proteases (SENPs) remains largely unexplored, and little is known about the regulation of SENPs themselves. Here, we show that a modest increase of reactive oxygen species (ROS) regulates SENP3 stability and localization. We found that SENP3 is continuously degraded through the ubiquitin-proteasome pathway under basal condition and that ROS inhibit this degradation. Furthermore, ROS causes SENP3 to redistribute from the nucleoli to the nucleoplasm, allowing it to regulate nuclear events. The stabilization and redistribution of SENP3 correlate with an increase in the transcriptional activity of the hypoxia-inducing factor-1 (HIF-1) under mild oxidative stress. ROS-enhanced HIF-1 transactivation is blocked by SENP3 knockdown. The de-SUMOylating activity of SENP3 is required for ROS-induced increase of HIF-1 transactivation, but the true substrate of SENP3 is the co-activator of HIF-1 alpha, p300, rather than HIF-1 alpha itself. Removing SUMO2/3 from p300 enhances its binding to HIF-1 alpha. In vivo nude mouse xenografts overexpressing SENP3 are more angiogenic. Taken together, our results identify SENP3 as a redox sensor that regulates HIF-1 transcriptional activity under oxidative stress through the de-SUMOylation of p300.
Huang
Chao
C
Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Han
Yan
Y
Wang
Yumei
Y
Sun
Xuxu
X
Yan
Shan
S
Yeh
Edward T H
ET
Chen
Yuying
Y
Cang
Hui
H
Li
Hui
H
Shi
Guiying
G
Cheng
Jinke
J
Tang
Xueming
X
Yi
Jing
J
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D025842:SUMO-1 Protein / Q000378:metabolism*; D015533:Transcriptional Activation
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D003546:Cysteine Endopeptidases; C499718:SENP3 protein, human
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