Elevated p62/SQSTM1 determines the fate of autophagy-deficient neural stem cells by increasing superoxide

Autophagy plays important roles in many biological processes, but our understanding of the mechanisms regulating stem cells by autophagy is limited. Interpretations of earlier studies of autophagy using knockouts of single genes are confounded by accumulating evidence for other functions of many aut...

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Bibliographic Details
Published in:The Journal of cell biology 2016-02, Vol.212 (5), p.545-560
Main Authors: Wang, Chenran, Chen, Song, Yeo, Syn, Karsli-Uzunbas, Gizem, White, Eileen, Mizushima, Noboru, Virgin, Herbert W, Guan, Jun-Lin
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Animals
Autophagy
Cellular biology
Genes
Heat-Shock Proteins - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neural Stem Cells - metabolism
Sequestosome-1 Protein
Stem cells
Superoxides - metabolism
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Summary:Autophagy plays important roles in many biological processes, but our understanding of the mechanisms regulating stem cells by autophagy is limited. Interpretations of earlier studies of autophagy using knockouts of single genes are confounded by accumulating evidence for other functions of many autophagy genes. Here, we show that, in contrast to Fip200 deletion, inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 does not impair the maintenance and differentiation of postnatal neural stem cells (NSCs). Only Fip200 deletion, but not Atg5, Atg16L1, or Atg7 deletion, caused p62/sequestome1 aggregates to accumulate in NSCs. Fip200 and p62 double conditional knockout mice demonstrated that p62 aggregate formation triggers aberrant superoxide increases by impairing superoxide dismutase functions. By comparing the inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 with Fip200 deletion, we revealed a critical role of increased p62 in determining the fate of autophagy-deficient NSCs through intracellular superoxide control.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201507023