USP13 deubiquitinates p62/SQSTM1 to induce autophagy and Nrf2 release for activating antioxidant response genes

SQSTM1/p62 (sequestosome 1) is a multifunctional protein that serves as a receptor for selective autophagy and scaffold. In selective autophagy, p62 functions as a bridge between polyubiquitinated proteins and autophagosomes. Further, p62 acts as a signaling hub for many cellular pathways including mTORC1, NF-kappa B, and Keap1Nrf2. Post-translational modifications of p62, such as ubiquitination and phosphorylation, are known to determine its binding partners and regulate their intracellular functions. However, the mechanism of p62 deubiquitination remains unclear. In this study, we found that ubiquitin-specific protease 13 (USP13), a member of the USP family, directly binds p62 and removes ubiquitin at Lys7 (K7) of the PB1 domain. USP13-mediated p62 deubiquitination enhances p62 protein stability and facilitates p62 oligomerization, resulting in increased autophagy and degradation of Keap1, which is a negative regulator of the antioxidant response that promotes Nrf2 activation. Thus, USP13 can be considered a therapeutic target as a deubiquitination enzyme of p62 in autophagy-related diseases.

Automated summary

This study found that ubiquitin-specific protease 13 (USP13) directly binds to p62 and removes its ubiquitination at Lys7 (K7) of the PB1 domain. Furthermore, the deubiquitination of p62 by USP13 enhances its stability, promotes p62 oligomerization, and increases autophagy and degradation of Keap1, leading to activation of Nrf2. Thus, USP13 can be considered a therapeutic target for autophagy-related diseases as a deubiquitination enzyme of p62.