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}
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 fip200hGFAP conditional knock-in (cKI) mice led to NSC deficiency, resembling the fip200hGFAP conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200hGFAP 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 fip200hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200hGFAP 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.
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.