三丁基锡通过Keap1的巨噬非依赖性减少激活Keap1- nrf2途径。

IF 1.8 4区 医学 Q4 TOXICOLOGY
Misaki Hatano, Shunichi Hatamiya, Masatsugu Miyara, Yaichiro Kotake
{"title":"三丁基锡通过Keap1的巨噬非依赖性减少激活Keap1- nrf2途径。","authors":"Misaki Hatano,&nbsp;Shunichi Hatamiya,&nbsp;Masatsugu Miyara,&nbsp;Yaichiro Kotake","doi":"10.2131/jts.48.161","DOIUrl":null,"url":null,"abstract":"<p><p>Tributyltin (TBT) is an environmental chemical, which was used as an antifouling agent for ships. Although its use has been banned, it is still persistently present in ocean sediments. Although TBT reportedly causes various toxicity in mammals, few studies on the mechanisms of biological response against TBT toxicity exist. The well-established Keap1-Nrf2 pathway is activated as a cytoprotective mechanism under stressful conditions. The relationship between TBT and the Keap1-Nrf2 pathway remains unclear. In the present study, we evaluated the effect of TBT on the Keap1-Nrf2 pathway. TBT reduced Keap1 protein expression in Neuro2a cells, a mouse neuroblastoma cell line, after 6 hr without altering mRNA expression levels. TBT also promoted the nuclear translocation of Nrf2, a transcription factor for antioxidant proteins, after 12 hr and augmented the expression of heme oxygenase 1, a downstream protein of Nrf2. Furthermore, TBT decreased Keap1 levels in mouse embryonic fibroblast (MEF) cells, with the knockout of Atg5, which is essential for macroautophagy, as well as in wild-type MEF cells. These results suggest that TBT activates the Keap1-Nrf2 pathway via the reduction in the Keap1 protein level in a macroautophagy-independent manner. The Keap1-Nrf2 pathway is activated by conformational changes in Keap1 induced by reactive oxygen species or electrophiles. Furthermore, any unutilized Keap1 protein is degraded by macroautophagy. Understanding the novel mechanism governing the macroautophagy-independent reduction in Keap1 by TBT may provide insights into the unresolved biological response mechanism against TBT toxicity and the activation mechanism of the Keap1-Nrf2 pathway.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 3","pages":"161-168"},"PeriodicalIF":1.8000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Tributyltin activates the Keap1-Nrf2 pathway via a macroautophagy-independent reduction in Keap1.\",\"authors\":\"Misaki Hatano,&nbsp;Shunichi Hatamiya,&nbsp;Masatsugu Miyara,&nbsp;Yaichiro Kotake\",\"doi\":\"10.2131/jts.48.161\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Tributyltin (TBT) is an environmental chemical, which was used as an antifouling agent for ships. Although its use has been banned, it is still persistently present in ocean sediments. Although TBT reportedly causes various toxicity in mammals, few studies on the mechanisms of biological response against TBT toxicity exist. The well-established Keap1-Nrf2 pathway is activated as a cytoprotective mechanism under stressful conditions. The relationship between TBT and the Keap1-Nrf2 pathway remains unclear. In the present study, we evaluated the effect of TBT on the Keap1-Nrf2 pathway. TBT reduced Keap1 protein expression in Neuro2a cells, a mouse neuroblastoma cell line, after 6 hr without altering mRNA expression levels. TBT also promoted the nuclear translocation of Nrf2, a transcription factor for antioxidant proteins, after 12 hr and augmented the expression of heme oxygenase 1, a downstream protein of Nrf2. Furthermore, TBT decreased Keap1 levels in mouse embryonic fibroblast (MEF) cells, with the knockout of Atg5, which is essential for macroautophagy, as well as in wild-type MEF cells. These results suggest that TBT activates the Keap1-Nrf2 pathway via the reduction in the Keap1 protein level in a macroautophagy-independent manner. The Keap1-Nrf2 pathway is activated by conformational changes in Keap1 induced by reactive oxygen species or electrophiles. Furthermore, any unutilized Keap1 protein is degraded by macroautophagy. Understanding the novel mechanism governing the macroautophagy-independent reduction in Keap1 by TBT may provide insights into the unresolved biological response mechanism against TBT toxicity and the activation mechanism of the Keap1-Nrf2 pathway.</p>\",\"PeriodicalId\":17654,\"journal\":{\"name\":\"Journal of Toxicological Sciences\",\"volume\":\"48 3\",\"pages\":\"161-168\"},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Toxicological Sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2131/jts.48.161\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"TOXICOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Toxicological Sciences","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2131/jts.48.161","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"TOXICOLOGY","Score":null,"Total":0}
引用次数: 1

摘要

三丁基锡(TBT)是一种环保化学品,被用作船舶防污剂。虽然它的使用已被禁止,但它仍然持续存在于海洋沉积物中。虽然有报道称TBT对哺乳动物具有多种毒性,但对TBT毒性生物反应机制的研究很少。已知的Keap1-Nrf2通路在应激条件下作为细胞保护机制被激活。TBT与Keap1-Nrf2通路之间的关系尚不清楚。在本研究中,我们评估了TBT对Keap1-Nrf2通路的影响。TBT降低了小鼠神经母细胞瘤细胞系Neuro2a细胞中Keap1蛋白的表达,作用6小时后未改变mRNA的表达水平。TBT还促进了抗氧化蛋白转录因子Nrf2在12小时后的核易位,并增加了Nrf2下游蛋白血红素加氧酶1的表达。此外,TBT还降低了小鼠胚胎成纤维细胞(MEF)中的Keap1水平,敲除了Atg5,而Atg5是巨噬所必需的,在野生型MEF细胞中也是如此。这些结果表明,TBT通过降低Keap1蛋白水平,以与巨噬无关的方式激活Keap1- nrf2途径。Keap1- nrf2通路是由活性氧或亲电试剂引起的Keap1构象变化激活的。此外,任何未被利用的Keap1蛋白都会被巨噬降解。了解TBT调控Keap1巨噬非依赖性减少的新机制,可能有助于了解尚未解决的TBT毒性生物学反应机制和Keap1- nrf2通路的激活机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tributyltin activates the Keap1-Nrf2 pathway via a macroautophagy-independent reduction in Keap1.

Tributyltin (TBT) is an environmental chemical, which was used as an antifouling agent for ships. Although its use has been banned, it is still persistently present in ocean sediments. Although TBT reportedly causes various toxicity in mammals, few studies on the mechanisms of biological response against TBT toxicity exist. The well-established Keap1-Nrf2 pathway is activated as a cytoprotective mechanism under stressful conditions. The relationship between TBT and the Keap1-Nrf2 pathway remains unclear. In the present study, we evaluated the effect of TBT on the Keap1-Nrf2 pathway. TBT reduced Keap1 protein expression in Neuro2a cells, a mouse neuroblastoma cell line, after 6 hr without altering mRNA expression levels. TBT also promoted the nuclear translocation of Nrf2, a transcription factor for antioxidant proteins, after 12 hr and augmented the expression of heme oxygenase 1, a downstream protein of Nrf2. Furthermore, TBT decreased Keap1 levels in mouse embryonic fibroblast (MEF) cells, with the knockout of Atg5, which is essential for macroautophagy, as well as in wild-type MEF cells. These results suggest that TBT activates the Keap1-Nrf2 pathway via the reduction in the Keap1 protein level in a macroautophagy-independent manner. The Keap1-Nrf2 pathway is activated by conformational changes in Keap1 induced by reactive oxygen species or electrophiles. Furthermore, any unutilized Keap1 protein is degraded by macroautophagy. Understanding the novel mechanism governing the macroautophagy-independent reduction in Keap1 by TBT may provide insights into the unresolved biological response mechanism against TBT toxicity and the activation mechanism of the Keap1-Nrf2 pathway.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
3.20
自引率
5.00%
发文量
53
审稿时长
4-8 weeks
期刊介绍: The Journal of Toxicological Sciences (J. Toxicol. Sci.) is a scientific journal that publishes research about the mechanisms and significance of the toxicity of substances, such as drugs, food additives, food contaminants and environmental pollutants. Papers on the toxicities and effects of extracts and mixtures containing unidentified compounds cannot be accepted as a general rule.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信