Metabolic but not transcriptional regulation by PKM2 is important for Natural Killer cell responses
AbstractNatural Killer (NK) cells have an important role in immune responses to viruses and tumours. Integrating changes in signal transduction pathways and cellular metabolism is essential for effective NK cells responses. The PKM2 isoform of the glycolytic enzyme Pyruvate Kinase Muscle has described roles in regulating glycolytic flux and signal transduction, especially gene transcription. While PKM2 expression is robustly induced in activated NK cells, mice lacking PKM2 in NK cells showed no defect in NK cell metabolism or anti-viral responses to MCMV infection. This maintenance of function is explained by compensatory PKM1 expression in PKM2-null NK cell cells demonstrating that PKM2 is not a signalling molecule in this immune cell type. To further investigate the role of PKM2 we forced the tetramerization of the protein with TEPP-46, which increases its catalytic activity while inhibiting any signalling functions mediated by mono/dimeric conformations. NK cells activated with TEPP-46 had reduced effector function due to TEPP-46-induced increases in oxidative stress. Overall, PKM2-regulated glycolytic metabolism and redox status, not transcriptional control, facilitate optimal NK cells responses.