title: Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy.
abstract: Autophagy is a cellular defense response to stress conditions, such as nutrient starvation. The type III phosphatidylinositol (PtdIns) 3-kinase, whose catalytic subunit is PIK3C3/VPS34, plays a critical role in intracellular membrane trafficking and autophagy induction. PIK3C3 forms multiple complexes and the ATG14-containing PIK3C3 is specifically involved in autophagy induction. Mechanistic target of rapamycin (MTOR) complex 1, MTORC1, is a key cellular nutrient sensor and integrator to stimulate anabolism and inhibit catabolism. Inactivation of TORC1 by nutrient starvation plays a critical role in autophagy induction. In this report we demonstrated that MTORC1 inactivation is critical for the activation of the autophagy-specific (ATG14-containing) PIK3C3 kinase, whereas it has no effect on ATG14-free PIK3C3 complexes. MTORC1 inhibits the PtdIns 3-kinase activity of ATG14-containing PIK3C3 by phosphorylating ATG14, which is required for PIK3C3 inhibition by MTORC1 both in vitro and in vivo. Our data suggest a mechanistic link between amino acid starvation and autophagy induction via the direct activation of the autophagy-specific PIK3C3 kinase.
authors.forename: Hai-Xin
authors.initials: HX
authors.lastname: Yuan
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Russell
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000596:Amino Acids / Q000172:deficiency; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D002478:Cells, Cultured; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006815:Hunger / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: C539000:ATG14 protein, human; D033942:Adaptor Proteins, Vesicular Transport; D000596:Amino Acids; D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D058546:Class III Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases