KRIT1 loss-of-function induces a sustained Nrf2-mediated adaptive homeostasis that sensitizes cells to oxidative stress: implication for Cerebral Cavernous Malformation disease

KRIT1 is a disease gene responsible for Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease of proven genetic origin affecting 0.3–0.5% of the population. Previously, we demonstrated that KRIT1 is involved in the control of intracellular redox homeostasis, suggesting that its loss-of-function may impair cell defense against oxidative stress. Here we found that KRIT1 loss induces a sustained redox-sensitive upregulation of the Nrf2 antioxidant defense pathway and its downstream target Glyoxalase 1 (Glo1), a pivotal stress-responsive defense enzyme involved in cellular protection against glycative and oxidative stress through the metabolism of methylglyoxal (MG). However, these effects were associated with a downregulation of major apoptosis-protective proteins, including MG-modified Hsp70 and Hsp27 proteins, and a consequent increased susceptibility to oxidative DNA damage and apoptosis. Overall, our data demonstrate that KRIT1 loss-of-function affects major mechanisms involved in adaptive responses to oxidative stress, leading to a sustained adaptive redox homeostasis that counteracts intrinsic oxidative stress but sensitizes cells to further oxidative challenges. These findings provide novel options for the development of targeted therapeutic strategies.