Nucleoredoxin regulates glucose metabolism via phosphofructokinase 1.

Phosphofructokinase (PFK) 1 is a glycolytic enzyme, and its abnormality contributes to the development of multiple human diseases, such as cancer. Here, we report that nucleoredoxin (NRX), a thioredoxin-related oxidoreductase, is a novel interacting partner of PFK1. NRX binds directly to PFK1, and endogenous NRX and PFK1 interact in vivo. In NRX(-/-) mouse embryonic fibroblasts (MEFs), the oligomerization status of PFK1 is altered and the catalytic activity of PFK1 is decreased. NRX deficiency augmented levels of NADPH and reduced glutathione, two major cellular antioxidants generated through the pentose phosphate pathway. Indeed, NRX(-/-) MEFs are significantly more resistant to oxidative stress than NRX(+/+) MEFs. These results reveal a novel role of NRX in the regulation of PFK1 activity and in the balance between glycolysis and the pentose phosphate pathway.