Investigating Peroxiredoxins Impact on AMPs

The Orr-Radyuk lab is interested in understanding the link between aging and genetic influences controlling the cell’s redox state, as determined by enzymes involved in reducing and oxidizing (redox) reactions. They have observed that Drosophila normally exhibit a shift towards a pro-oxidizing cellular environment and spikes in AMP levels, independent of infections, when they reach old age. Additionally, peroxiredoxins (PRXs), a family of thiol-dependent peroxidases, have been shown to impact lifespan, and regulate the same pro-oxidizing shift seen in advanced age. Beyond their peroxidase functions, RXRs can also interact with signaling pathways related to immunity. Previous data showed that PRXs influence the IMD inflammatory pathway, resulting in an age associated increase in antimicrobial peptide (AMP) expression, independent of infection. Specifically, past research has shown that a reduction of mitochondrial PRXs (dPrx3 and dPrx5) causes a spike in AMPs during old age and rapid aging leading to early death. This report shows a reduction of ER localized Prx4 in addition to a reduction of Prx3/Prx5 mitigated the age associated AMP expression but didn’t alter the rapid aging phenotype. Thus, a PRX associated redox signal seems to require dPrx 4 to be transferred from the mitochondrial to the ER and finally the nucleus to drive AMP expression. Further studies are needed to elucidate if dPrx4 remains in the ER lumen and interacts with unfolded-protein-response (UPR) membrane proteins, or if dPrx4 leaves the ER under conditions of cellular oxidative stress to interact directly with IMD pathway enzymes