Department of Public Health, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Department of Public Health, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Biochem Biophys Res Commun. 2022 Jun 18;609:134-140. doi: 10.1016/j.bbrc.2022.04.019. Epub 2022 Apr 10.
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.
SQSTM1/p62，以下简称 p62，是一种应激诱导的细胞蛋白，可与各种信号蛋白以及泛素化蛋白相互作用，调节多种细胞功能和细胞存活。甲基汞（MeHg）暴露会增加 p62 的水平，后者在 MeHg 诱导的毒性中发挥保护作用。然而，p62 缓解 MeHg 毒性的潜在机制仍知之甚少。在此，我们报告了 p62 与神经前体细胞表达的发育下调蛋白 4（NEDD4）的相互作用，NEDD4 是一种 HECT E3 泛素连接酶。NEDD4 结合的 p62 区域位于脯氨酸和精氨酸（PR）丰富区域（氨基酸：102-119），Phox 和 Bem1（PB1）结构域的 C 端延伸。为了评估 p62-NEDD4 复合物的重要性，我们研究了缺失突变体（GFP-Δ102-119 p62）在 MEFs 中对内源性 p62 缺失的补偿作用。与 GFP-Δ102-119 p62/p62KO 细胞相比，用 MeHg 处理后 GFP-p62/p62KO 细胞的细胞活力明显更高。我们的发现表明，通过 p62-NEDD4 复合物的形成，可以缓解 MeHg 毒性的新机制。
