药理抑制 USP14 能以蛋白酶体依赖但狐狸依赖的方式延缓与蛋白稳态相关的衰老。

Jin Ju Lim, Sujin Noh, Woojun Kang, Bom Hyun, Byung-Hoon Lee, Seogang Hyun
{"title":"药理抑制 USP14 能以蛋白酶体依赖但狐狸依赖的方式延缓与蛋白稳态相关的衰老。","authors":"Jin Ju Lim, Sujin Noh, Woojun Kang, Bom Hyun, Byung-Hoon Lee, Seogang Hyun","doi":"10.1080/15548627.2024.2389607","DOIUrl":null,"url":null,"abstract":"<p><p>Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in <i>Drosophila</i> and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging <i>Drosophila</i> flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by <i>foxo</i> mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.<b>Abbreviations</b>: AAAs: amino acid analogs; foxo: forkhead box, sub-group O; IFMs: indirect flight muscles; UPS: ubiquitin-proteasome system; USP14: ubiquitin specific peptidase 14.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner.\",\"authors\":\"Jin Ju Lim, Sujin Noh, Woojun Kang, Bom Hyun, Byung-Hoon Lee, Seogang Hyun\",\"doi\":\"10.1080/15548627.2024.2389607\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in <i>Drosophila</i> and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging <i>Drosophila</i> flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by <i>foxo</i> mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.<b>Abbreviations</b>: AAAs: amino acid analogs; foxo: forkhead box, sub-group O; IFMs: indirect flight muscles; UPS: ubiquitin-proteasome system; USP14: ubiquitin specific peptidase 14.</p>\",\"PeriodicalId\":93893,\"journal\":{\"name\":\"Autophagy\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Autophagy\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1080/15548627.2024.2389607\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Autophagy","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1080/15548627.2024.2389607","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

衰老往往伴随着蛋白稳态的下降,表现为错误折叠蛋白聚集倾向的增加,而泛素-蛋白酶体系统(UPS)和大自噬/自噬等蛋白质量控制系统可以防止错误折叠蛋白聚集。虽然泛素-蛋白酶体系统和自噬在减缓年龄诱导的蛋白稳态衰退中的作用已被阐明,但关于如何以协作方式激活这些途径以延缓蛋白稳态相关衰老的信息却很有限。在这里,我们展示了利用 IU1 通过药理抑制 USP14(泛素特异性肽酶 14)来激活 UPS,从而改善果蝇和人类细胞中因衰老或蛋白稳态压力而导致的蛋白稳态和自噬衰退。用 IU1 治疗不仅能缓解衰老果蝇飞行肌肉中多泛素化蛋白质的聚集,还能通过同时激活 UPS 和自噬,延长果蝇的寿命并增强其运动能力。有趣的是,当蛋白酶体活性受到抑制时,这种药物的作用消失了,但当 foxo 基因突变导致蛋白稳态破坏时,这种作用却很明显。总之,我们的研究结果揭示了有效改善与蛋白稳态紊乱相关的年龄相关病症的潜在策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner.

Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.Abbreviations: AAAs: amino acid analogs; foxo: forkhead box, sub-group O; IFMs: indirect flight muscles; UPS: ubiquitin-proteasome system; USP14: ubiquitin specific peptidase 14.

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
自引率
0.00%
发文量
0
×
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