Pyruvate kinase M2 (PKM2) interacts with activating transcription factor 2 (ATF2) to bridge glycolysis and pyroptosis in microglia.

Abstract

Pyruvate kinase M2 (PKM2), a glycolytic rate-limiting enzyme, reportedly plays an important role in tumorigenesis and the inflammatory response by regulating the metabolic reprogramming. However, its contribution to microglial activation during neuroinflammation is still unknown. In this study, we observed an enhanced glycolysis level in the lipopolysaccharide (LPS)-activated microglia. Utilizing the glycolysis inhibitor 2-DG, we proved that LPS requires glycolysis to induce microglial pyroptosis. Moreover, the protein expression, dimer/monomer formation, phosphorylation and nuclear translocation of PKM2 were all increased by LPS. Silencing PKM2 or preventing its nuclear translocation by TEPP-46 significantly alleviated the LPS-induced inflammatory response and pyroptosis in microglia. Employing biological mass spectrometry combined with immunoprecipitation technology, we identified for the first time that PKM2 interacts with activating transcription factor 2 (ATF2) in microglia. Inhibition of glycolysis or preventing PKM2 nuclear aggregation significantly reduced the phosphorylation and activation of ATF2. Furthermore, knocking down ATF2 reduced the LPS-induced pyroptosis of microglia. In vivo, we showed the LPS-induced pyroptosis in the cerebral cortex tissues of mice, and first found that an increased PKM2 expression was co-localized with ATF2 in the inflamed mice brain. Collectively, our data suggested for the first time that PKM2, a key rate-limiting enzyme of the Warburg effect, directly interacts with the pro-inflammatory transcription factor ATF2 to bridge glycolysis and pyroptosis in microglia, which might be a pivotal crosstalk between metabolic reprogramming and neuroinflammation in the CNS.

• Authors: Mengmeng Li, Hongjian Lu, Xueyan Wang, Chengwei Duan, Xiangyang Zhu, Yi Zhang, Xin Ge, Feng Ji, Xueqin Wang, Jianbin Su, Dongmei Zhang
• Journal: Molecular immunology (Mol Immunol) Vol. 140 Pg. 250-266 (12 2021) ISSN: 1872-9142 [Electronic] England
• PMID: 34798593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Activating Transcription Factor 2
• Lipopolysaccharides
• Pyruvate Kinase

Topics

• Activating Transcription Factor 2 (metabolism)
• Aerobiosis
• Animals
• Brain (pathology)
• Cell Line
• Cell Nucleus (metabolism)
• Gene Silencing
• Glycolysis
• Inflammation (pathology)
• Lipopolysaccharides
• Male
• Mice, Inbred C57BL
• Microglia (metabolism, pathology)
• Phosphorylation
• Protein Binding
• Protein Transport
• Pyroptosis
• Pyruvate Kinase (metabolism)
• Up-Regulation