title: Regulation of nutrient-sensitive autophagy by uncoordinated 51-like kinases 1 and 2.
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.
authors.affiliation: London Research Institute, Cancer Research UK, Secretory Pathways Laboratory, London, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: McAlpine
authors.forename: Leon E
authors.initials: LE
authors.lastname: Williamson
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Tooze
authors.forename: Edmond Y W
authors.initials: EY
authors.lastname: Chan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D000077191:Wortmannin
chemical_list: D000596:Amino Acids; D000730:Androstadienes; D034741:RNA, Small Interfering; C401061:Ulk2 protein, mouse; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C112444:Ulk1 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D000077191:Wortmannin
keywords: MEF; ULK1; ULK2; WIPI1; WIPI2; knockout; nutrient starvation