title: ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase.
abstract: Autophagy is the primary cellular catabolic program activated in response to nutrient starvation. Initiation of autophagy, particularly by amino-acid withdrawal, requires the ULK kinases. Despite its pivotal role in autophagy initiation, little is known about the mechanisms by which ULK promotes autophagy. Here we describe a molecular mechanism linking ULK to the pro-autophagic lipid kinase VPS34. Following amino-acid starvation or mTOR inhibition, the activated ULK1 phosphorylates Beclin-1 on Ser 14, thereby enhancing the activity of the ATG14L-containing VPS34 complexes. The Beclin-1 Ser 14 phosphorylation by ULK is required for full autophagic induction in mammals and this requirement is conserved in Caenorhabditis elegans. Our study reveals a molecular link from ULK1 to activation of the autophagy-specific VPS34 complex and autophagy induction.
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Russell
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.forename: Haixin
authors.initials: H
authors.lastname: Yuan
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Park
authors.forename: Yu-Yun
authors.initials: YY
authors.lastname: Chang
authors.forename: Joungmok
authors.initials: J
authors.lastname: Kim
authors.forename: Haerin
authors.initials: H
authors.lastname: Kim
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Neufeld
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000596:Amino Acids / Q000172:deficiency; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D017173:Caenorhabditis elegans; D002478:Cells, Cultured; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013217:Starvation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D000596:Amino Acids; D051017:Apoptosis Regulatory Proteins; C561107:Atg14 protein, mouse; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C428743:Rb1cc1 protein, mouse; D025521:Tumor Suppressor Proteins; C512859:UVRAG protein, mouse; D033921:Vesicular Transport Proteins; D012694:Serine; C546843:mTOR protein, mouse; D058546:Class III Phosphatidylinositol 3-Kinases; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C112444:Ulk1 protein, mouse