Protective function of the SQSTM1/p62-NEDD4 complex against methylmercury toxicity.

SQSTM1/p62, hereinafter referred to as p62, is a stress-induced cellular protein that interacts with various signaling proteins as well as ubiquitinated proteins to regulate a variety of cellular functions and cell survival. Methylmercury (MeHg) exposure increases the levels of p62, the latter playing a protective role in MeHg-induced toxicity. However, the underlying mechanism by which p62 alleviates MeHg toxicity remains poorly understood. Herein, we report the interaction of p62 with neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4), a HECT E3 ubiquitin ligase. The region of p62 where NEDD4 binds is located at the proline- and arginine (PR)-rich region (amino acids: 102-119), C-terminal extension of the Phox and Bem1 (PB1) domain. To evaluate the importance of the p62-NEDD4 complex, we examined the compensation of deletion mutant (GFP-Δ102-119 p62) for the lack of endogenous p62 in MEFs. GFP-p62/p62KO cells exhibited significantly higher cell viability than GFP-Δ102-119 p62/p62KO cells after treatment with MeHg. Our findings suggest novel mechanisms to alleviate MeHg toxicity through p62-NEDD4 complex formation.