Abstract:
Extensive research has demonstrated that autophagy is instrumental in various biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Intriguingly, while the complete deletion of Fip200 severely impairs NSC maintenance and differentiation, the inhibition of canonical autophagy via deletion of core genes like Atg5, Atg16l1, and Atg7, or through blocking FIP200's canonical interaction with ATG13 (designated as the FIP200-4A mutant or FIP200 KI), shows no such detrimental effects. This highlights the likely critical role of FIP200’s non-canonical functions, whose mechanisms have remained elusive until now. Here, utilizing genetic mouse models, we demonstrate that FIP200 mediates non-canonical autophagy degradation of p62/sequestome1 mainly via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200GFAP cKI mice led to NSC deficiency, resembling the phenotype of fip200GFAP cKO mice. Remarkably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200GFAP cKI mice but also led to a marked reduction in p62 aggregates accumulation. A TAX1BP1 mutant unable to bind to FIP200 or NBR1/p62 failed to achieve this rescue. Furthermore, conditional deletion of Tax1bp1 in fip200GFAP cKO mice led to more serious NSC deficiency and p62 aggregates accumulation compared with fip200GFAP cKO mice. Collectively, these findings illuminate the essential role of the FIP200-TAX1BP1 axis in mediating non-canonical autophagy degradation of p62 aggregates for NSC maintenance and function, offering new therapeutic targets for neurodegenerative diseases.
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