Regulation of nutrient-sensitive autophagy by uncoordinated 51-like kinases 1 and 2

McAlpine, Fiona and Williamson, Leon E and Tooze, Sharon A and Chan, Edmond Y W (2013) Regulation of nutrient-sensitive autophagy by uncoordinated 51-like kinases 1 and 2. Autophagy, 9 (3). 361 - 373. (https://doi.org/10.4161/auto.23066)

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Abstract

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.

ORCID iDs

McAlpine, Fiona, Williamson, Leon E ORCID logoORCID: https://orcid.org/0000-0002-1594-8131, Tooze, Sharon A and Chan, Edmond Y W;
CORE (COnnecting REpositories)