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bioRxiv · 10.1101/709105

NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system

Komatsu, M.·Sanchez-Martin, P.·Kageyama, S.·Sou, Y.-S.
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Abstract

p62/SQSTM1 is a multivalent protein that has an ability to cause a 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 BRCA1 gene 1 (NBR1), an autophagy receptor structurally similar to p62/SQSTM1, in the p62-liquid droplet formation and the Keap1-Nrf2 pathway. The overexpression of NBR1 blocked selective degradation of p62/SQSTM1 through autophagy and promoted the accumulation and phosphorylation of p62/SQSTM1 in liquid-like bodies, which is required for the activation of Nrf2. NBR1 was induced in response to oxidative stress, and then the p62-mediated Nrf2 activation was up-regulated. Conversely, loss of Nbr1 suppresses not only the formation of p62/SQSTM1-liquid droplets but also p62-dependent Nrf2 activation during oxidative stress. Taken together, our results show that NBR1 mediates p62/SQSTM1-liquid droplet formation to activate the Keap1-Nrf2 pathway.

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Komatsu, M., Sanchez-Martin, P., Kageyama, S., Sou, Y.-S.. 2019-07-19. NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system. https://doi.org/10.1101/709105

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