USP13 enhances the function of p62/SQSTM1 by increasing its stability and aggregate formation

Abstract

Abstract p62/SQSTM1 is a multifunctional protein that serves as a receptor protein for selective autophagy and a scaffold protein. In selective autophagy, p62 functions as a bridge between poly-ubiquitinated proteins and the autophagosome. In addition, p62 acts as a signaling hub for many cellular pathways, including mTORC1, NF-κB, and Keap1-Nrf2. These functions are regulated by post-translational modification of p62. In particular, changes in the binding partner or intracellular function of p62 by phosphorylation or ubiquitination are well studied. However, the opposite process of the p62 ubiquitination, the deubiquitination mechanism is still unclear. It was hypothesized that the unknown pathway of p62 deubiquitination might regulate its stability and functions. In this study, it was found that ubiquitin-specific protease 13 (USP13), one of the USP family, directly bound to p62 and removed ubiquitination at its PB1 domain. The deubiquitinated p62 by USP13 was enhanced the stability and the aggregate formation. Furthermore, increased p62 aggregation by USP13 activated autophagy and inhibited Keap1 from functioning as a negative regulator of Nrf2. Consequently, activated Nrf2 increased its migration to nucleus and acted as a transcription factor, increasing the expression of the antioxidant response gene. Taken together, USP13 enhanced the stability and aggregate formation of p62, which activated autophagy and antioxidant response.