Sequestosome1/p62 protects mouse embryonic fibroblasts against low-dose methylercury-induced cytotoxicity and is involved in clearance of ubiquitinated proteins.
Sequestosome1/p62 protects mouse embryonic fibroblasts against low-dose methylercury-induced cytotoxicity and is involved in clearance of ubiquitinated proteins.
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DOI：
10.1038/s41598-017-17112-8
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发表时间：
2017-12-01
影响因子：
4.6
通讯作者：
Kiyono M
中科院分区：
文献类型：
--
作者：
Takanezawa Y;Nakamura R;Harada R;Sone Y;Uraguchi S;Kiyono M
甲基汞（MeHg）是一种广泛分布的环境污染物，可引起一系列细胞毒性效应。然而，甲基汞毒性的分子机制尚未完全了解。在这里，我们报告说，螯合体1/p62保护小鼠胚胎成纤维细胞（MEFs）对低剂量的甲基汞细胞毒性通过清除甲基汞诱导的泛素化蛋白。甲基汞暴露可暂时诱导MEFs中p62 mRNA和蛋白的表达。p62缺陷型MEFs对甲基汞暴露的敏感性高于野生型（WT）MEFs。与WT MEFs相比，在p62缺陷细胞中检测到更早和更高水平的泛素化蛋白积累。共聚焦显微镜显示，p62和泛素化蛋白共同定位在MEFs的核周区域的甲基汞处理后。MEFs的进一步分析显示，泛素化蛋白与LC 3阳性斑点共同定位后，与甲基汞和氯喹，自噬抑制剂的共同治疗。相反，在p62缺陷的MEFs中存在最小的共定位。本研究首次研究了低剂量甲基汞暴露后细胞中p62和泛素化蛋白的表达和分布。我们的研究结果表明，p62是至关重要的细胞保护对甲基汞诱导的毒性，是必要的甲基汞诱导的泛素化蛋白清除。
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.
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DOI：
10.1073/pnas.0504136102
发表时间：
2005-07-05
影响因子：
11.1
作者：
Fox, MD;Snyder, AZ;Raichle, ME
通讯作者：
Raichle, ME
影响因子：
4.9
作者：
Dichter GS;Damiano CA;Allen JA
通讯作者：
Allen JA
影响因子：
3.2
作者：
Laird AR;Fox PM;Eickhoff SB;Turner JA;Ray KL;McKay DR;Glahn DC;Beckmann CF;Smith SM;Fox PT
通讯作者：
Fox PT
影响因子：
4.8
作者：
Posner, Jonathan;Marsh, Rachel;Maia, Tiago V.;Peterson, Bradley S.;Gruber, Allison;Simpson, H. Blair
通讯作者：
Simpson, H. Blair
基于ICA的人工制品去除和加速fMRI获取，以改善静止状态网络成像。
影响因子：
5.7
作者：
Griffanti L;Salimi-Khorshidi G;Beckmann CF;Auerbach EJ;Douaud G;Sexton CE;Zsoldos E;Ebmeier KP;Filippini N;Mackay CE;Moeller S;Xu J;Yacoub E;Baselli G;Ugurbil K;Miller KL;Smith SM
通讯作者：
Smith SM