A role for peroxiredoxins in H(2)O(2)- and MEKK-dependent activation of the p38 signaling pathway

The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in the cellular response to various stresses and its deregulation accompanies pathological conditions such as cancer and chronic inflammation. Hydrogen peroxide (H(2)O(2)) is a well-established activator of the p38 MAPK signaling pathway. However, the mechanisms of H(2)O(2)-induced p38 activation are not yet fully understood. In Drosophila cells, we find that H(2)O(2)-induced activation of p38 depends on the MAPK kinase kinase (MAP3K) Mekk1. In line with the emerging role of peroxiredoxins as H(2)O(2) sensors and signal transmitters we observe an H(2)O(2)-dependent interaction between Mekk1 and the cytosolic peroxiredoxin of Drosophila, Jafrac1. In human cells, MEKK4 (the homologue of Mekk1) and peroxiredoxin-2 (Prx2) interact in a similar manner, suggesting an evolutionarily conserved mechanism. In both organisms, H(2)O(2) induces transient disulfide-linked conjugates between the MAP3K and a typical 2-Cys peroxiredoxin. We propose that these conjugates represent the relaying of oxidative equivalents from H(2)O(2) to the MAP3K and that the oxidation of Mekk1/MEKK4 leads to the downstream activation of p38 MAPK. Indeed, the depletion of cytosolic 2-Cys peroxiredoxins in human cells diminished H(2)O(2)-induced activation of p38 MAPK.