Novel nuclear translocation and phosphorylation of IκB kinase alpha (IKKα) by oxidative stress after transient cerebral ischemia

초록

The IκB kinase (IKK) complex is a converging point in the classic NF-κB activation pathway, and tightly controls NF-κB activation, which is a principal transcriptional regulator of diverse oxidative stress. We previously showed decreases in mRNA and protein levels in the IKK complex after 30 min of transient focal cerebral ischemia (tFCI). IKK knockout (KO) mice were shown to have reduced infarct. However, the biochemical function and subcellular location of IKKα during cerebral ischemia are not well understood. To clarify the role of reactive oxygen species (ROS) in IKKα after tFCI, we investigated subcellular localization and function of IKKα in wild-type mice and superoxide dismutase (SOD1) KO mice, which feature high ROS levels and increased intracellular ROS. We observed a marked nuclear accumulation and phosphorylation of IKKα 1 hour after 30 min of tFCI in the SOD1 KO mice, which was concomitant with the expression of phosphorylated NF-κB p65 and the inhibitory protein IκBα in the nucleus. Reduction in SOD1 levels increased infarct volume and oxidatively damaged proteins such as carbonylated proteins, and 4-hydroxy-2-nonenal-conjugated proteins. These data demonstrate that nuclear translocation of IKKα by oxidative stress may have a distinct function from the canovial NF-κB activation pathway. We suggest that the increased oxidative stress may exacerbate ischemic brain injury via this new nuclear role for IKKα.