Wang et al. explain why loss of the autophagy-initiating protein Fip200 alters the fate of neural stem cells (NSCs).
Fip200 is required to induce the formation of autophagosomes that engulf and recycle cytoplasmic components. NSCs lacking Fip200 fail to self-renew or differentiate properly, possibly because, in the absence of autophagy, they accumulate mitochondria that emit increased amounts of reactive oxygen species. Fip200 has other, nonautophagic functions, however, so, to learn more about how its loss affects NSC fate, Wang et al. examined the effects of removing other genes required for autophagy.
To their surprise, the researchers found that NSCs self-renewed and differentiated normally in the absence of Atg5, Atg16L1, or Atg7, even though, in each case, autophagy was impaired and the cells still accumulated mitochondria. One notable difference, however, was that only Fip200-deficient NSCs accumulated cytoplasmic aggregates of the selective autophagy receptor p62. Knocking out p62 restored the ability of Fip200-null NSCs to self-renew and differentiate in vivo.
Wang et al. found that p62 aggregation impaired the activity of the enzyme superoxide dismutase 1 (SOD1), preventing the removal of superoxide species released from mitochondria. Restoring SOD activity lowered superoxide levels and rescued the defects of Fip200-deficient NSCs.
Senior author Jun-Lin Guan says it remains unclear why, at least in NSCs, p62 only accumulates in the absence of Fip200, but not other autophagy regulators. Fip200 might regulate p62 levels through a nonautophagic mechanism, or NSCs lacking Atg5, Atg16L1, or Atg7 might retain some autophagic activity that can degrade the receptor.