The two faces of peroxiredoxins

Highlights by Larissa A. C. Carvalho

In the antiquity, many cities protected their territories by surrounding fortifications, with giant gates and arches working as unique gateways. The Roman god Janus, known as the protector of entrances or new-beginnings, is represented by a head with two faces in opposite directions. The two faces of Janus symbolize the duality of nature. Well, nature itself is marked by dichotomy. What in nature cannot be good and bad at the same time? That is the origin of the term Janus effect.

A remarkable example of the Janus effect is the mustard gas (1,1-thiobis-2-chloroethane). Used as a chemical weapon during World War I, it causes serious inflammation of the skin and painful blisters. In high-exposition levels, it acutely causes blindness and destroys the lungs’ alveoli, killing the exposed victim. But, what a coincidence: during World War II, the mustard gas showed its therapeutic face. In 1943, the Liberty ship carrying such gas suffered an attack. The survivors were treated by doctor Cornelius Rhoads, who noticed a dramatic drop in the number of white blood cells, attributing it to the mustard gas inhaled by the crew members. The doctor suggested the use of this compound to treat cancer, especially leukemia, where the increase of leukocytes is brutal. Although nowadays other compounds are safer and more effective than mustard gas, this serves as a reminder of how many compounds can be rediscovered after their first reported effects.

It is well established that the role of peroxiredoxins is to eliminate H₂O₂ by directly discharging the oxidative equivalents to the thioredoxin system. However, for the first time, Sobotta and colleagues [1] described a new role for human peroxiredoxin 2 as a redox signaling pathway. At the same time it plays its role of detoxifying the organism, it relays oxidative equivalents to a transcription factor, STAT3, inactivating it In response to cytokines and growth factors, STAT3 mediates the expression of many prostimulatory genes such as thos related to cell growth and apoptosis, playing a key role in many cellular processes.

In the past, peroxiredoxins have been found to be associated with many signaling complexes, but it always has been assumed that its association is of a non-specific type or that its role is to remove H₂O₂ and to protect other proteins from oxidation damage. However, depending on location and context, peroxiredoxins may switch between thioredoxin and other proteins, acting as a dual-face protein: playing scavenging and signaling modes. Therefore, the anti- and pro-oxidant pathways (scavenging and signaling) may be inextricably interconnected through thiol peroxidases. Notwithstanding, could the peroxiredoxin be a new example of the Janus effect? Well, like Barry Halliwell and John Gutteridge wrote in their book Free radicals in biology and medicine, the Neil Young’s song and an undeniable truth: The same thing that makes you live, can kill you in the end.

1. M. C. Sobotta, W. Liou, S. Stocker, D. Talwar, M. Oehler, T. Ruppert, A. N. Scharf, T. P. Dick. Peroxiredoxin-2 and STAT3 form a redox relay for H₂O₂ signaling Nature Chemical Biology, 11(1): 64-70, 2015 | doi: 10.1038/nchembio.1695

Larissa Anastácio da Costa Carvalho is a PhD Student from the laboratory of Redox Processes in Inflammatory Response, Instituto de Química da USP, coordinated by Flavia C. Meotti