Transglutaminase 2 regulates redox homeostasis by inhibiting NRF2 degradation in keratinocytes

Abstract

Unbalanced antioxidant homeostasis results in overproduction of reactive oxygen species (ROS) triggering cellular damage and apoptosis. We have reported that Transglutaminase 2 (TG2) is activated by ROS, and TG2 has an anti-apoptotic effect against ROS. However, the molecular mechanism of TG2 in redox regulation is unknown. To examine whether TG2 is required for antioxidative defense system, we established a TG2 deficient keratinocyte HaCaT cell lines and tested the effects upon ROS homeostasis. As a result, TG2 deficient HaCaT cells exposed to tert-butyl hydroperoxide (tBHP), showed high levels of intracellular ROS. In addition, TG2 deficient HaCaT cells showed reduced total GSH levels, a GSH reduction capacity, and reduced protein levels of its glutamate cysteine ligase catalytic subunit (Gclc) that was caused by increased proteasomal degradation of Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Collectively, our observations indicate that TG2 in keratinocytes increases antioxidative signaling pathways and its ability to regulate redox homeostasis. This suggests that TG2 may function to ensure cell survival under oxidative stress conditions.