Macroautophagy, commonly referred to as autophagy, is a protein degradation pathway that occurs constitutively in cells, but can also be induced by stressors such as nutrient
starvation or
protein aggregation. Autophagy has been implicated in multiple disease mechanisms including neurodegeneration and
cancer, with both
tumor suppressive and oncogenic roles. Uncoordinated 51-like
kinase 1 (ULK1) is a critical autophagy
protein near the apex of the hierarchal regulatory pathway that receives signals from the master nutrient sensors MTOR and
AMP-activated protein kinase (AMPK). In mammals, ULK1 has a close homolog, ULK2, although their functional distinctions have been unclear. Here, we show that ULK1 and ULK2 both function to support autophagy activation following nutrient
starvation. Increased autophagy following
amino acid or
glucose starvation was disrupted only upon combined loss of ULK1 and ULK2 in mouse embryonic fibroblasts. Generation of
PtdIns3P and recruitment of WIPI2 or ZFYVE1/DFCP1 to the phagophore following
amino acid starvation was blocked by combined Ulk1/2 double knockout. Autophagy activation following
glucose starvation did not involve recruitment of either WIPI1 or WIPI2 to forming autophagosomes. Consistent with a PtdIns3P-independent mechanism,
glucose-dependent autophagy was resistant to
wortmannin. Our findings support functional redundancy between ULK1 and ULK2 for nutrient-dependent activation of autophagy and furthermore highlight the differential pathways that respond to
amino acid and
glucose deprivation.