The pentose phosphate pathway is a metabolic redox sensor and regulates transcription during the antioxidant response

A shift in primary carbon metabolism is the fastest response to oxidative stress. Induced within seconds, it precedes transcriptional regulation, and produces reducing equivalents in form of NADPH within the pentose phosphate pathway (PPP).

Here, we provide evidence for a regulatory signaling function of this metabolic transition in yeast. Several PPP-deficiencies caused abnormal accumulation of intermediate metabolites during the stress response. These PPP-deficient strains had strong growth deficits on media containing oxidants, but we observed that part of their oxidant-phenotypes were not attributable to the production of NADPH equivalents. This pointed to a second, yet unknown role of the PPP in the antioxidant response. Comparing transcriptome profiles obtained by RNA sequencing, we found gene expression profiles that resembled oxidative conditions when PPP activity was increased. Vice versa, deletion of PPP enzymes disturbed and delayed mRNA and protein expression during the antioxidant response.

Thus, the transient activation of the PPP is a metabolic signal required for balancing and timing gene expression upon an oxidative burst.

Consequently, dynamic rearrangements in central carbon metabolism seem to be of major importance for eukaryotic redox sensing, and represent a novel class of dynamic gene expression regulators.