Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
Methylmercury (MeHg) is a widespread environmental pollutant and causes a serious hazard to health worldwide. Macroautophagy (hereafter referred to as autophagy), a major and highly conserved degradation pathway in eukaryotes, prevents the accumulation of misfolded or damaged proteins, protein aggregates, and damaged organelles in the cytoplasm. We previously demonstrated that MeHg exposure promotes autophagy, and Atg5-dependent autophagy serves to protect cells from MeHg cytotoxicity. Moreover, we found that sequestosome1/p62 protects cells against low-dose MeHg cytotoxicity via clearance of MeHg-induced ubiquitinated proteins. Our findings suggest that p62 is crucial for cytoprotection against MeHg-induced toxicity.
Treatment with low-dose MeHg induced the expression of endoplasmic reticulum (ER) stress (CHOP and GADD34). p62KO MEFs exhibited significantly higher CHOP and GADD34 mRNA induction following MeHg treatment compared to their wild-type (WT) counterparts. The endogenous expression of GFP-p62 was fully compensated for the lack of p62 because of the mild induction of ER stress response in p62KO MEFs. These results suggest that p62 plays a critical role not only in the clearance of ubiquitinated proteins but also in attenuation of MeHg-induced ER stress. In this symposium, we will discuss our recent experimental findings of the role of p62 on autophagic response and ER stress following MeHg exposure.
