TAX1BP1和FIP200协调p62聚集体的非规范自噬,促进小鼠神经干细胞的维持。

IF 4 1区 生物学 Q1 ZOOLOGY
Yi-Fu Zhu, Rong-Hua Yu, Shuai Zhou, Pei-Pei Tang, Rui Zhang, Yu-Xin Wu, Ran Xu, Jia-Ming Wei, Ying-Ying Wang, Jia-Li Zhang, Meng-Ke Li, Xiao-Jing Shi, Yu-Wei Zhang, Guang-Zhi Liu, Rick F Thorne, Xu Dong Zhang, Mian Wu, Song Chen
{"title":"TAX1BP1和FIP200协调p62聚集体的非规范自噬,促进小鼠神经干细胞的维持。","authors":"Yi-Fu Zhu, Rong-Hua Yu, Shuai Zhou, Pei-Pei Tang, Rui Zhang, Yu-Xin Wu, Ran Xu, Jia-Ming Wei, Ying-Ying Wang, Jia-Li Zhang, Meng-Ke Li, Xiao-Jing Shi, Yu-Wei Zhang, Guang-Zhi Liu, Rick F Thorne, Xu Dong Zhang, Mian Wu, Song Chen","doi":"10.24272/j.issn.2095-8137.2024.021","DOIUrl":null,"url":null,"abstract":"<p><p>Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of <i>Fip200</i> severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as <i>Atg5</i>, <i>Atg16l1</i>, and <i>Atg7</i>, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of <i>Tax1bp1</i> in <i>fip200</i> <sup><i>hGFAP</i></sup> conditional knock-in (cKI) mice led to NSC deficiency, resembling the <i>fip200</i> <sup><i>hGFAP</i></sup> conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from <i>tax1bp1</i>-knockout <i>fip200</i> <sup><i>hGFAP</i></sup> cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of <i>Tax1bp1</i> in <i>fip200</i> <sup><i>hGFAP</i></sup> cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to <i>fip200</i> <sup><i>hGFAP</i></sup> cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.</p>","PeriodicalId":48636,"journal":{"name":"Zoological Research","volume":"45 4","pages":"937-950"},"PeriodicalIF":4.0000,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11298671/pdf/","citationCount":"0","resultStr":"{\"title\":\"TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance.\",\"authors\":\"Yi-Fu Zhu, Rong-Hua Yu, Shuai Zhou, Pei-Pei Tang, Rui Zhang, Yu-Xin Wu, Ran Xu, Jia-Ming Wei, Ying-Ying Wang, Jia-Li Zhang, Meng-Ke Li, Xiao-Jing Shi, Yu-Wei Zhang, Guang-Zhi Liu, Rick F Thorne, Xu Dong Zhang, Mian Wu, Song Chen\",\"doi\":\"10.24272/j.issn.2095-8137.2024.021\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of <i>Fip200</i> severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as <i>Atg5</i>, <i>Atg16l1</i>, and <i>Atg7</i>, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of <i>Tax1bp1</i> in <i>fip200</i> <sup><i>hGFAP</i></sup> conditional knock-in (cKI) mice led to NSC deficiency, resembling the <i>fip200</i> <sup><i>hGFAP</i></sup> conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from <i>tax1bp1</i>-knockout <i>fip200</i> <sup><i>hGFAP</i></sup> cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of <i>Tax1bp1</i> in <i>fip200</i> <sup><i>hGFAP</i></sup> cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to <i>fip200</i> <sup><i>hGFAP</i></sup> cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.</p>\",\"PeriodicalId\":48636,\"journal\":{\"name\":\"Zoological Research\",\"volume\":\"45 4\",\"pages\":\"937-950\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-07-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11298671/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Zoological Research\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.24272/j.issn.2095-8137.2024.021\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ZOOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Zoological Research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.24272/j.issn.2095-8137.2024.021","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ZOOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

自噬在多种生物过程中发挥着关键作用,包括神经干细胞(NSC)的维持和分化。有趣的是,虽然完全缺失 Fip200 会严重影响 NSC 的维持和分化,但通过缺失 Atg5、Atg16l1 和 Atg7 等核心基因或阻断 FIP200 和 ATG13 之间的典型相互作用(称为 FIP200-4A 突变体或 FIP200 KI)来抑制典型自噬并不会产生类似的有害影响。这凸显了 FIP200 的非规范功能可能具有关键性的参与作用,而其作用机制至今仍难以捉摸。在这里,我们利用遗传小鼠模型证明了 FIP200 主要通过 TAX1BP1 在 NSCs 中介导 p62/sequestome1 的非规范自噬降解。在 fip200 hGFAP 条件性基因敲入(cKI)小鼠中有条件地缺失 Tax1bp1 会导致 NSC 缺乏,类似于 fip200 hGFAP 条件性基因敲除(cKO)小鼠的表型。值得注意的是,重新引入野生型 TAX1BP1 不仅能恢复来自 tax1bp1 基因敲除 fip200 hGFAP cKI 小鼠的 NSCs 的维持能力,还能显著减少 p62 聚合体的积累。相反,无法与 FIP200 或 NBR1/p62 结合的 TAX1BP1 突变体则无法实现这种恢复。此外,与 fip200 hGFAP cKO 小鼠相比,在 fip200 hGFAP cKO 小鼠中条件性地缺失 Tax1bp1 会加剧 NSC 缺乏和 p62 聚合体积聚。总之,这些发现说明了FIP200-TAX1BP1轴在介导p62聚集体的非经典自噬降解以维持NSC和功能方面的重要作用,为神经退行性疾病提供了新的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance.

Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of Fip200 severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as Atg5, Atg16l1, and Atg7, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200 hGFAP conditional knock-in (cKI) mice led to NSC deficiency, resembling the fip200 hGFAP conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200 hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of Tax1bp1 in fip200 hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200 hGFAP cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.

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
Zoological Research
Zoological Research Medicine-General Medicine
CiteScore
7.60
自引率
10.20%
发文量
1937
审稿时长
8 weeks
期刊介绍: Established in 1980, Zoological Research (ZR) is a bimonthly publication produced by Kunming Institute of Zoology, the Chinese Academy of Sciences, and the China Zoological Society. It publishes peer-reviewed original research article/review/report/note/letter to the editor/editorial in English on Primates and Animal Models, Conservation and Utilization of Animal Resources, and Animal Diversity and Evolution.
×
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