The p38 Pathway Regulates Oxidative Stress Tolerance by Phosphorylation of Mitochondrial Protein IscU

Background: The p38 pathway is an evolutionarily conserved signaling pathway that responds to a variety of stresses. Results: dIscU can be phosphorylated by dMK2, thereby impacting mitochondrial respiratory complex I activity. Conclusion: Iron-sulfur cluster protein IscU phosphorylation by MK2 downstream of p38 signaling may regulate oxidative stress tolerance. Significance: IscU is a novel substrate of MK2, mechanistically connecting the p38 pathway and mitochondria iron-sulfur clusters for the first time. The p38 pathway is an evolutionarily conserved signaling pathway that responds to a variety of stresses. However, the underlying mechanisms are largely unknown. In the present study, we demonstrate that p38b is a major p38 MAPK involved in the regulation of oxidative stress tolerance in addition to p38a and p38c in Drosophila. We further show the importance of MK2 as a p38-activated downstream kinase in resistance to oxidative stresses. Furthermore, we identified the iron-sulfur cluster scaffold protein IscU as a new substrate of MK2 both in Drosophila cells and in mammalian cells. These results imply a new mechanistic connection between the p38 pathway and mitochondria iron-sulfur clusters.