SUMO1 negatively regulates reactive oxygen species production from NADPH oxidases.
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.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.Together, these results suggest that SUMO is an important regulatory mechanism that indirectly represses the production of ROS to ameliorate cellular stress.
Mesh Terms:
Anacardic Acids, Analysis of Variance, Animals, COS Cells, Calcium, Cercopithecus aethiops, Down-Regulation, HEK293 Cells, Humans, Isoenzymes, Lysine, Muscle, Smooth, Vascular, Mutation, Myocytes, Smooth Muscle, NADPH Oxidase, Neutrophils, Oxidative Stress, Phosphorylation, Protein Processing, Post-Translational, Protein Stability, RNA Interference, Reactive Oxygen Species, SUMO-1 Protein, Sumoylation, Time Factors, Transfection, Ubiquitin-Conjugating Enzymes
Anacardic Acids, Analysis of Variance, Animals, COS Cells, Calcium, Cercopithecus aethiops, Down-Regulation, HEK293 Cells, Humans, Isoenzymes, Lysine, Muscle, Smooth, Vascular, Mutation, Myocytes, Smooth Muscle, NADPH Oxidase, Neutrophils, Oxidative Stress, Phosphorylation, Protein Processing, Post-Translational, Protein Stability, RNA Interference, Reactive Oxygen Species, SUMO-1 Protein, Sumoylation, Time Factors, Transfection, Ubiquitin-Conjugating Enzymes
Arterioscler. Thromb. Vasc. Biol.
Date: Jul. 01, 2011
PubMed ID: 21527745
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