tert‐Butylhydroquinone‐induced formation of high‐molecular‐weight p62: A novel mechanism in the activation of Nrf2‐Keap1

Abstract The respiratory system is always exposed to air and is most vulnerable to attack by environmental free radicals. The nuclear factor E2‐related factor 2–Kelch‐like ECH‐associated protein 1–antioxidant response element (Nrf2‐Keap1‐ARE) pathway and p62 are both involved in the oxidative stress response. However, the interplay between these two systems remains largely unknown. This study shows that treatment of L2 cells with tert‐Butylhydroquinone (tBHQ) generates a high‐molecular‐weight (HMW) form of p62, leading to activation of the Nrf2‐Keap1‐ARE pathway. The levels of HMW‐p62 increased as the tBHQ concentration increased, with concomitant decreases seen in the classical form of p62. Moreover, small interfering RNA targeting p62 increases Keap1 protein levels and inactivates the Nrf2‐Keap1‐ARE pathway. These results demonstrate that the Nrf2‐Keap1 pathway is partially regulated by p62. tBHQ‐induced HMW‐p62 production may be a novel mechanism in the activation of the Nrf2‐Keap1‐ARE pathway.