Abstract
Methylmercury (MeHg) is a widely distributed environmental pollutant that causes a series of cytotoxic effects. However, molecular mechanisms underlying MeHg toxicity are not fully understood. Here, we report that sequestosome1/p62 protects mouse embryonic fibroblasts (MEFs) against low-dose MeHg cytotoxicity via clearance of MeHg-induced ubiquitinated proteins. p62 mRNA and protein expression in MEFs were temporally induced by MeHg exposure p62-deficient MEFs exhibited higher sensitivity to MeHg exposure compared to their wild-type (WT) counterparts. An earlier and higher level of accumulation of ubiquitinated proteins was detected in p62-deficient cells compared with WT MEFs. Confocal microscopy revealed that p62 and ubiquitinated proteins co-localized in the perinuclear region of MEFs following MeHg treatment. Further analysis of MEFs revealed that ubiquitinated proteins co-localized with LC3-positive puncta upon co-treatment with MeHg and chloroquine, an autophagy inhibitor. In contrast, there was minimal co-localization in p62-deficient MEFs. The present study, for the first time, examined the expression and distribution of p62 and ubiquitinated proteins in cells exposed to low-dose MeHg. Our findings suggest that p62 is crucial for cytoprotection against MeHg-induced toxicity and is required for MeHg-induced ubiquitinated protein clearance.
Highlights
Mercury released into aquatic environments by natural events and various anthropogenic activities is readily methylated by microorganisms[1]
We showed that MeHg stimulated autophagy in mouse embryonic fibroblasts (MEFs) cells, but increased the p62 protein levels in several types of cells such as MEFs, Caco-2, and SH SY-5Y9
To confirm the involvement of p62 in MeHg-induced autophagy, we examined the distribution of ubiquitinated proteins and LC3 puncta in wild-type and p62 knockout (p62KO) MEFs
Summary
Mercury released into aquatic environments by natural events and various anthropogenic activities is readily methylated by microorganisms[1]. The molecular responses and effects of low doses of MeHg to which humans are exposed through daily food intake are not well-understood. We recently showed that a low dose of MeHg activates autophagy in several cell types, and the lack of autophagy gene 5 (Atg5) makes cells more sensitive to MeHg toxicity[9]. These findings suggest an association between autophagy and protective mechanisms against low-dose MeHg toxicity. The increased microtubule-associated protein 1 light chain (LC3)-II/LC3-I ratio and increased autophagic vacuoles in human neuronal stem cells after MeHg exposure suggest possible upregulation in autophagic activity[12]. P62 is an inducible protein in response to various stressors[18,19]
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