SUMO1 Negatively Regulates Reactive Oxygen Species Production From NADPH Oxidases

被引:53
作者
Pandey, Deepesh [1 ]
Chen, Feng [1 ]
Patel, Anand [1 ]
Wang, Cong-Yi [2 ]
Dimitropoulou, Christiana [3 ]
Patel, Vijay S. [5 ]
Rudic, R. Daniel [3 ]
Stepp, David W. [1 ,4 ]
Fulton, David J. [1 ,3 ]
机构
[1] Med Coll Georgia, Vasc Biol Ctr, Augusta, GA 30912 USA
[2] Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA 30912 USA
[3] Med Coll Georgia, Dept Pharmacol, Augusta, GA 30912 USA
[4] Med Coll Georgia, Dept Physiol, Augusta, GA 30912 USA
[5] Med Coll Georgia, Dept Cardiothorac & Vasc Surg, Augusta, GA 30912 USA
基金
美国国家卫生研究院;
关键词
endothelium; reactive oxygen species; signal transduction; stress; vascular biology; PROTEIN SUMOYLATION; OXIDATIVE STRESS; SUPEROXIDE ANION; IN-VIVO; EXPRESSION; PATHWAY; NOX; ROS; TRANSCRIPTION; LOCALIZATION;
D O I
10.1161/ATVBAHA.111.226621
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective-Increased protein SUMOylation (small ubiquitin-related modifier [ SUMO]) provides protection from cellular stress, including oxidative stress, but the mechanisms involved are incompletely understood. The NADPH oxidases (Nox) are a primary source of reactive oxygen species (ROS) and oxidative stress, and thus our goal was to determine whether SUMO regulates NADPH oxidase activity. Methods and Results-Increased expression of SUMO1 potently inhibited the activity of Nox1 to Nox5. In contrast, inhibition of endogenous SUMOylation with small interfering RNA to SUMO1 or ubiquitin conjugating enzyme 9 or with the inhibitor anacardic acid increased ROS production from human embryonic kidney-Nox5 cells, human vascular smooth muscle cells, and neutrophils. The suppression of ROS production was unique to SUMO1, and it required a C-terminal diglycine and the SUMO-specific conjugating enzyme ubiquitin conjugating enzyme 9. SUMO1 did not modify intracellular calcium or Nox5 phosphorylation but reduced ROS output in an isolated enzyme assay, suggesting direct effects of SUMOylation on enzyme activity. However, we could not detect the presence of SUMO1 conjugation on Nox5 using a variety of approaches. Moreover, the mutation of more than 17 predicted and conserved lysine residues on Nox5 did not alter the inhibitory actions of SUMO1. Conclusion-Together, these results suggest that SUMO is an important regulatory mechanism that indirectly represses the production of ROS to ameliorate cellular stress. (Arterioscler Thromb Vasc Biol. 2011; 31:1634-1642.)
引用
收藏
页码:1634 / U380
页数:13
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