title: Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy.
abstract: Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiation and progression of autophagy. The class II enzyme emerged only recently as an alternative source of PtdIns3P and autophagic initiator. However, the orthodox paradigm is challenged by findings that the PIK3CB catalytic subunit of class I PI3K acts as a positive regulator of autophagy, and PIK3C3 was thought to be an amino acid sensor for MTOR, which curbs autophagy. At present, a number of PtdIns3K and PI3K inhibitors, including specific PIK3C3 inhibitors, have been developed for suppression of autophagy and for clinical applications in autophagy-related human diseases.
authors.affiliation: a Department of Biochemistry; Yong Loo Lin School of Medicine, National University of Singapore ; Singapore.
authors.forename: Xinlei
authors.initials: X
authors.lastname: Yu
authors.affiliation: a Department of Biochemistry; Yong Loo Lin School of Medicine, National University of Singapore ; Singapore.
authors.forename: Yun Chau
authors.initials: YC
authors.lastname: Long
authors.affiliation: b Department of Physiology; Yong Loo Lin School of Medicine, National University of Singapore ; Singapore.
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D046912:Multiprotein Complexes; D010716:Phosphatidylinositols; D058546:Class III Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: MTOR; PI3K; PI3K inhibitor; PIK3C3; autophagy