Non-canonical function of FIP200 is required for neural stem cell maintenance and differentiation by limiting TBK1 activation and p62 aggregate formation

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 Fip200(hGFAP) 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.