Lysine Methyltransferase SETD7 (SET7/9) Regulates ROS Signaling through mitochondria and NFE2L2/ARE pathway

• Published in: Scientific reports Vol. 5; no. 1; p. 14368
• Main Authors: He, Shuying, Owen, Dafydd R., Jelinsky, Scott A., Lin, Lih-Ling
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-10-2015; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/21; 13/89; 13/95; 14/63; 38; 38/90; 45/41; 631/154/433; 631/250/256; 631/337/176; 631/80/304; 96/34; 96/44; Antioxidant Response Elements; Antioxidants; Catalase - genetics; Catalase - metabolism; Cell Line; Chronic obstructive pulmonary disease; Cytokines; Cytokines - genetics; Cytokines - metabolism; Disease; Enzymes; Gene Expression; Gene Expression Regulation; Gene Knockdown Techniques; Gene regulation; Histone-Lysine N-Methyltransferase - physiology; Homeostasis; Humanities and Social Sciences; Humans; Inflammation; Lysine; Macrophages; Metabolism; Methylation; Methyltransferase; Mitochondria; Mitochondria - enzymology; Mitochondrial Dynamics; multidisciplinary; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; NF-κB protein; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Proteins; R&D; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research & development; Science; Signal Transduction; siRNA; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Transcription Factors - metabolism; Up-Regulation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep14368

Reactive oxygen species (ROS) homeostasis requires stringent regulation. ROS imbalance, especially ROS accumulation, has profound implications in various disease pathogenesis. Lysine methylation of histone and non-histone proteins has been implicated in various cellular responses. The main objective of this study is to investigate the role of SET domain containing lysine methyltransferase SETD7 (SET7/9) in the regulation of ROS-mediated signaling. Here we report that inhibition of SETD7 with siRNA or a SETD7 small molecule inhibitor in both macrophages and a human bronchial epithelial cell line (Beas-2B) were able to counter NF-ĸB-induced oxidative stress and pro-inflammatory cytokine production. Meanwhile, inhibition of SETD7 elevates mitochondria antioxidant functions
via
negative regulation of PPARGC1A and NFE2L2. Using a co-expression system and purified proteins, we detected direct interaction between SETD7 and NFE2L2. These results indicate that lysine methylation by SETD7 is important for the fine-tuning of ROS signaling through its regulation on pro-inflammatory responses, mitochondrial function and the NFE2L2/ARE pathway. Up-regulation of multiple antioxidant genes and improved ROS clearance by inhibition of SETD7 suggests the potential benefit of targeting SETD7 in treating ROS-associated diseases.