TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance  

作　　者：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 FThorne Xu Dong Zhang Mian Wu Song Chen 

机构地区：[1]School of Life Sciences,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei,Anhui 230001,China [2]Translational Research Institute of Henan Provincial People’s Hospital and People'’s Hospital of Zhengzhou University,Tianjian Laboratory of Advanced Biomedical Sciences,Academy of Medical Sciences,Zhengzhou University,Zhengzhou,Henan 450053,China [3]Institute of Medicinal Biotechnology,Jiangsu College of Nursing,Huai’an,Jiangsu 223300,China [4]Laboratory Animal Center,Academy of Medical Science,Zhengzhou University,Zhengzhou,Henan 450052,China [5]Henan Key Laboratory of Stem cell Differentiation and Modification,Henan Provincial People’s Hospital,Henan University,Zhengzhou,Henan 450053,China [6]School of Biomedical Sciences and Pharmacy,The University of Newcastle,NSW 2308,Australia

出　　处：《Zoological Research》2024年第4期937-950,共14页动物学研究（英文）

基　　金：National Natural Science Foundation of China(U2004138,81773132,81820108021);University Excellent Teaching Team of“Qinglan Project”in Jiangsu Province(2022-25);Henan Province Key Research and Development Project(232102521028);Excellent Youth Foundation of Henan Scientific Committee(21230040016)。

摘　　要：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.

关 键 词：Non-canonical autophagy TAX1BP1 FIP200 P62 AGGREGATES Neural stem cell 

分 类 号：Q421[生物学—神经生物学]