Loss of KRIT1 causes a sustained activation of an adaptive cellular allostatic response that counteracts intrinsic oxidative stress but sensitizes cells to further oxidative challenges

KRIT1 (CCM1) is a disease gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease affecting 0.3–0.5% of the population. Previously, we demonstrated that KRIT1 loss-of-function is associated with altered ROS homeostasis, activation of the redox-sensitive transcription factor c-Jun, and increased cell sensitivity to oxidative stress, raising the possibility that KRIT1 dysfunction exerts pleiotropic effects on multiple redox-sensitive mechanisms. To address this possibility, we investigated redox-sensitive systems that play a critical role in cellular responses to oxidative stress, including the master NRF2 antioxidant defense pathway and its downstream targets, including Heme Oxygenase-1 (HO-1) and Glyoxalase 1 (GLO1). The outcomes of our experiments showed that KRIT1 loss-of-function induces a redox-sensitive adaptive upregulation of NRF2, HO-1 and GLO1, resulting in a sustained cellular allostatic response that counteracts intrinsic oxidative stress but sensitizes cells to further oxidative challenges. While extending the pleiotropic functions of KRIT1, these findings shed new light on the mechanistic relationship between KRIT1 loss-of-function and enhanced cell susceptibility to oxidative damage, thus providing valuable new insights into CCM pathogenesis and novel options for the development of preventive and therapeutic strategies.