NBR 1‐mediated p62‐liquid droplets enhance the Keap1‐Nrf2 system

p62/ SQSTM 1 is a multivalent protein that has the ability to cause liquid–liquid phase separation and serves as a receptor protein that participates in cargo isolation during selective autophagy. This protein is also involved in the non‐canonical activation of the Keap1‐Nrf2 system, a major oxidative stress response pathway. Here, we show a role of neighbor of BRCA 1 gene 1 ( NBR 1), an autophagy receptor structurally similar to p62/ SQSTM 1, in p62‐liquid droplet formation and Keap1‐Nrf2 pathway activation. Overexpression of NBR 1 blocks selective degradation of p62/ SQSTM 1 through autophagy and promotes the accumulation and phosphorylation of p62/ SQSTM 1 in liquid‐like bodies, which is required for the activation of Nrf2. NBR 1 is induced in response to oxidative stress, which triggers p62‐mediated Nrf2 activation. Conversely, loss of Nbr1 suppresses not only the formation of p62/ SQSTM 1‐liquid droplets, but also of p62‐dependent Nrf2 activation during oxidative stress. Taken together, our results show that NBR 1 mediates p62/ SQSTM 1‐liquid droplet formation to activate the Keap1‐Nrf2 pathway.