ROS elevate HIF-1α phosphorylation for insect lifespan through the CK2-MKP3-p38 pathway.

Diapause in insects is akin to dauer in Caenorhabditis elegans and hibernation in vertebrates, characterized by metabolic depression and lifespan extension. Previous studies have shown that reactive oxygen species (ROS) and hypoxia-inducible factor-1α (HIF-1α) in brains of diapause-destined pupae are more abundant than those in nondiapause-destined pupae in Helicoverpa armigera, but the ROS regulating HIF-1α activity remain unknown. Here, we showed that high ROS levels in brains of diapause-destined pupae resulted in low casein kinase 2 (CK2) activity and that downregulation of CK2 caused low expression of mitogen-activated protein kinase phosphatase 3 (MKP3), which is an inhibitor of p-p38. Thus, high p-p38 levels accumulate to improve HIF-1α activity via activating HIF-1α phosphorylation at the S732 residue to regulate insect diapause. This is the first report showing that a new pathway, ROS-CK2-MKP3-p38, regulates HIF-1α activity for lifespan in insects.