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

Shuying He1, Dafydd R Owen2, Scott A Jelinsky1

  • 1Inflammation and Immunology Research Unit, Pfizer Research, Cambridge, MA 02139.

Scientific Reports
|October 6, 2015
PubMed

Insights

Inhibiting SETD7 (SET domain containing lysine methyltransferase SETD7) reduces oxidative stress and inflammation by improving mitochondrial function. This suggests targeting SETD7 could treat diseases linked to reactive oxygen species (ROS) imbalance.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Medicine

Background:

  • Reactive oxygen species (ROS) homeostasis is critical for cellular function, and its imbalance, particularly accumulation, contributes to disease pathogenesis.
  • Lysine methylation, a post-translational modification, plays a role in cellular responses, but its specific involvement in ROS regulation is not fully understood.

Purpose of the Study:

  • To investigate the role of SET domain containing lysine methyltransferase SETD7 (SETD7) in regulating ROS-mediated signaling pathways.
  • To explore the therapeutic potential of targeting SETD7 in ROS-associated diseases.

Main Methods:

  • Utilized siRNA and a small molecule inhibitor to inhibit SETD7 activity in macrophages and Beas-2B cells.
  • Investigated the effects of SETD7 inhibition on NF-κB-induced oxidative stress, pro-inflammatory cytokine production, and mitochondrial antioxidant functions.
  • Examined the regulation of PPARGC1A and NFE2L2 by SETD7 and detected direct interaction between SETD7 and NFE2L2 using co-expression systems and purified proteins.

Main Results:

  • Inhibition of SETD7 effectively countered NF-κB-induced oxidative stress and pro-inflammatory cytokine production.
  • SETD7 inhibition enhanced mitochondrial antioxidant functions through negative regulation of PPARGC1A and NFE2L2.
  • Direct interaction between SETD7 and NFE2L2 was confirmed, indicating SETD7's role in the NFE2L2/ARE pathway.

Conclusions:

  • Lysine methylation by SETD7 is crucial for fine-tuning ROS signaling, impacting inflammatory responses and mitochondrial function.
  • Inhibition of SETD7 leads to the upregulation of antioxidant genes and improved ROS clearance.
  • Targeting SETD7 presents a potential therapeutic strategy for treating diseases associated with ROS imbalance.

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