KRIT1 Regulates the Homeostasis of Intracellular Reactive Oxygen Species.

KRIT1 is a gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhage. Comprehensive analysis of the KRIT1 gene in CCM patients has suggested that KRIT1 function needs to be severely impaired for pathogenesis. However, the molecular and cellular functions of KRIT1 as well as CCM pathogenesis mechanisms are still research challenges. We found that KRIT1 plays a role in molecular mechanisms involved in the maintenance of the intracellular Reactive Oxygen Species (ROS) homeostasis to prevent oxidative cellular damage. In particular, we demonstrate that KRIT1 loss/down-regulation is associated with a significant increase of intracellular ROS levels. Conversely, ROS levels in KRIT1-/- cells are significantly, and dose-dependently reduced after restoration of KRIT1 expression. Moreover, we show that the enhanced ROS levels observed in KRIT1-/- cells are associated with a significant increase in both cell proliferation rate and susceptibility to oxidative damage of cellular components, including DNA. Finally, we demonstrate that KRIT1 regulates the expression and activity of FoxO1, a transcription factor involved in defence mechanisms against oxidative stress, as well as of the antioxidant protein SOD2. Taken together, our results point to a model where KRIT1 regulates the steady-state levels of intracellular oxidants to prevent oxidative damage by regulating FoxO1 and SOD2 levels, thus providing an useful framework for understanding the molecular mechanisms of CCM pathogenesis.