AMPK-activated ULK1 phosphorylates PIKFYVE to drive formation of PtdIns5P-containing autophagosomes during glucose starvation.

The induction of macroautophagy/autophagy upon glucose deprivation can occur independently of the PIK3C3/VPS34 complex. Recently, we described a non-canonical signaling pathway involving the kinases AMPK, ULK1 and PIKFYVE that are induced during glucose starvation, leading to the formation of PtdIns5P-containing autophagosomes, resulting in increased autophagy flux and clearance of autophagy substrates. In this cascade, the activation of AMPK leads to ULK1 phosphorylation. ULK1 then phosphorylates PIKFYVE at S1548, leading to its activation and increased PtdIns5P formation, which enables the recruitment of machinery required for autophagosome biogenesis.