Abstract
FIP200 is an essential autophagy gene implicated in the regulation of postnatal neural progenitor/stem cells (NSCs). However, the contribution of FIP200’s canonical-autophagy function and its non-canonical functions to postnatal NSC maintenance remains unclear. Utilizing a recently generated Fip200-4A allele that specifically impairs FIP200’s canonical-autophagy function, we found that non-canonical functions of FIP200 was required for regulation of mouse NSC maintenance and neurogenesis in vivo. Ablating the non-canonical functions of FIP200, but not its autophagy function, increased TBK1 activation and p62 phosphorylation at S403 in NSCs. Phosphorylation of p62 was dependent on TBK1 kinase activity and increased the propensity of p62 aggregate formation specifically in FIP200-null NSCs. Accordingly, inhibition of TBK1 by amlexanox reduced p62 aggregates and restored NSC maintenance and differentiation in Fip200hGFAP cKO mice. These results reveal a mechanism for the non-canonical functions of FIP200 in NSC maintenance and differentiation by limiting TBK1 activation and subsequently, p62 aggregate formation.
Highlights
FIP200 is an essential autophagy gene implicated in the regulation of postnatal neural progenitor/ stem cells (NSCs)
In contrast to observations in neurons, we found recently that whereas deletion of FIP200 led to the gradual depletion of NSCs and their defective neurogenesis, NSCs tolerated the loss of other autophagy genes including Atg[5], Atg[7] and Atg16L1 without exhibiting any apparent phenotypes[16,17]
TBK1 phosphorylation of p62 increased its aggregates formation in FIP200-null NSCs, whereas inhibiting TBK1 reduced p62 aggregates and restored NSC maintenance and differentiation in Fip200hGFAP cKO mice. These results reveal a mechanism for the non-canonical functions of FIP200 to regulate NSC maintenance and differentiation by limiting TBK1 activation and its phosphorylation of p62 for ubiquitin aggregates formation
Summary
FIP200 is an essential autophagy gene implicated in the regulation of postnatal neural progenitor/ stem cells (NSCs). Ablating the non-canonical functions of FIP200, but not its autophagy function, increased TBK1 activation and p62 phosphorylation at S403 in NSCs. Phosphorylation of p62 was dependent on TBK1 kinase activity and increased the propensity of p62 aggregate formation in FIP200-null NSCs. inhibition of TBK1 by amlexanox reduced p62 aggregates and restored NSC maintenance and differentiation in Fip200hGFAP cKO mice. Autophagy dysfunction is implicated in a variety of diseases such as cancers, autoimmune diseases and neurodegenerative d iseases[9,10,11,12] It plays an especially critical role in post-mitotic cells such as neurons, which cannot dilute protein aggregates and damaged organelles through cell division. Multiple studies have shown that deletion of different autophagy genes such as Atg[5], Atg[7] and FIP200 in neurons caused increased ubiquitinated protein aggregates and neurodegenerative d efects[13,14,15]. Unlike other regions of the brain, p62 aggregates were detected in NSCs after deletion of FIP200, but not Atg[5], Atg16L1, or Atg[7], and deletion of p62 rescued NSC defects in Fip[200] cKO mice, suggesting a critical role of p62 aggregate formation in mediating defective NSC maintenance and neurogenesis[17]
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