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Inhibition of NF-κB Signaling by the Reactive Glycolytic Metabolite Methylglyoxal
Caroline Stanton1,2, Woojin Choi1, R Luke Wiseman2
1Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Abstract:
The NF-κB family of transcription factor complexes are central regulators of inflammation, and their dysregulation contributes to the pathology of multiple inflammatory disease conditions. Accordingly, identifying pharmacological mechanisms that restrain NF-κB overactivation remains an area of key importance. Here, we demonstrate that inhibition of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) with the small molecule inhibitor CBR-470-2 results in attenuated NF-κB signaling, decreasing transcriptional output in response to several canonical NF-κB activating stimuli. Mechanistically, PGK1 inhibition promotes the accumulation of the glycolytic metabolite methylglyoxal, which crosslinks and inactivates NF-κB proteins, limiting the phosphorylation and nuclear translocation of these transcription factor complexes. This work establishes a key connection between central carbon metabolism and immune signaling and further supports the notion that PGK1 inhibition may be a viable strategy to increase cellular survival and dampen inflammation in disease.
Insights
Inhibiting phosphoglycerate kinase 1 (PGK1) reduces inflammation by blocking NF-κB signaling. This occurs as PGK1 inhibition leads to methylglyoxal accumulation, which inactivates NF-κB proteins.
Area of Science:
- Immunology
- Metabolic pathways
- Molecular biology
Background:
- Nuclear factor kappa B (NF-κB) transcription factors are key regulators of inflammation.
- Dysregulated NF-κB signaling is implicated in various inflammatory diseases.
- Targeting NF-κB overactivation is crucial for therapeutic interventions.
Purpose of the Study:
- To investigate the role of phosphoglycerate kinase 1 (PGK1) in regulating NF-κB signaling.
- To explore the potential of PGK1 inhibition as a strategy to control inflammation.
Main Methods:
- Utilized the small molecule inhibitor CBR-470-2 to inhibit PGK1 activity.
- Assessed NF-κB signaling pathways and transcriptional output.
- Analyzed the accumulation of glycolytic metabolites, specifically methylglyoxal.
Main Results:
- PGK1 inhibition with CBR-470-2 attenuated NF-κB signaling.
- Reduced transcriptional output was observed in response to NF-κB activating stimuli.
- PGK1 inhibition led to methylglyoxal accumulation, causing crosslinking and inactivation of NF-κB proteins.
- Inhibition of NF-κB phosphorylation and nuclear translocation was observed.
Conclusions:
- PGK1 is a critical link between central carbon metabolism and immune signaling.
- PGK1 inhibition effectively dampens NF-κB-driven inflammation.
- Targeting PGK1 may offer a therapeutic strategy for inflammatory diseases.
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