Peroxide detection system

Homes are safeguarded by smoke detectors and carbon monoxide detectors. On page 779, Phalen et al. find that cells are likewise protected by a peroxide-monitoring system. Instead of beeping, this detector forms oligomers to alert cells to dangerous levels of H₂O₂.

H₂O₂ is a helpful signaling molecule, but at high concentrations it can also be a damaging reactive oxygen species. One family of antioxidant enzymes that hydrolyze—and thus neutralize—H₂O₂ is the peroxiredoxins (Prxs). The 2-Cys class of Prxs are inhibited by H₂O₂-mediated hyperoxidation. Scientists originally thought this negative feedback permitted H₂O₂ to accumulate to signaling-competent concentrations.

The new results show that signaling occurs at H₂O₂ concentrations that are too low to inactivate Prxs. Here, signaling was measured as growth factor–induced mitotic progression, which depends on H₂O₂ production. Cells responded to growth factors just fine without Prx inactivation.

At higher H₂O₂ levels, however, PrxII underwent a sudden shift in conformation. As PrxII became hyperoxidized, it formed cytoplasmic filaments. Progression through the cell cycle halted until PrxII was reduced and the filaments had dissolved.

The authors have more recently identified several PrxII-interacting proteins, one of which is known to relocate from the cytoplasm to the nucleus during H₂O₂ stress. They hypothesize that hyperoxidation and oligomerization of PrxII might liberate its interacting factors, which are then free to activate stress responses that stop the cell cycle and start recovery programs, eventually culminating in PrxII reduction. The group now plans to test the response of the interacting proteins to changes in the PrxII oxidation state.

The peroxide alarm might be silenced in cancerous cells, some of which have abnormally low PrxII levels. This deficiency might help to explain how these cells avoid mitotic arrest and apoptosis upon oxidative damage.