class IA phosphatidylinositol 3-kinase p110-β subunit is a positive regulator of autophagy

• Published in: The Journal of cell biology Vol. 191; no. 4; pp. 827 - 843
• Main Authors: Dou, Zhixun, Chattopadhyay, Mohar, Pan, Ji-An, Guerriero, Jennifer L, Jiang, Ya-Ping, Ballou, Lisa M, Yue, Zhenyu, Lin, Richard Z, Zong, Wei-Xing
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 15.11.2010; Rockefeller University Press
• Subjects: Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Animals; Antibodies; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy - physiology; Autophagy-Related Proteins; Beclin-1; Cell lines; Cells, Cultured; Class Ia Phosphatidylinositol 3-Kinase - genetics; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Class III Phosphatidylinositol 3-Kinases - genetics; Class III Phosphatidylinositol 3-Kinases - metabolism; Embryo, Mammalian - anatomy & histology; Embryo, Mammalian - physiology; Enzyme Inhibitors - metabolism; Fibroblasts - cytology; Fibroblasts - physiology; Fluorescence; Heart - physiology; HEK293 Cells; HT29 cells; Humans; Immunoprecipitation; Liver; Liver - cytology; Liver - physiology; Mice; Mice, Knockout; Microscopes; Phagosomes - metabolism; Phosphatidylinositol Phosphates - metabolism; Phosphatidylinositols; Physiological regulation; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Quantification; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Signal Transduction - physiology
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201006056

Autophagy is an evolutionarily conserved cell renewal process that depends on phosphatidylinositol 3-phosphate (PtdIns(3)P). In metazoans, autophagy is inhibited by PtdIns(3,4,5)P₃, the product of class IA PI3Ks, which mediates the activation of the Akt-TOR kinase cascade. However, the precise function of class IA PI3Ks in autophagy remains undetermined. Class IA PI3Ks are heterodimeric proteins consisting of an 85-kD regulatory subunit and a 110-kD catalytic subunit. Here we show that the class IA p110-β catalytic subunit is a positive regulator of autophagy. Genetic deletion of p110-β results in impaired autophagy in mouse embryonic fibroblasts, liver, and heart. p110-β does not promote autophagy by affecting the Akt-TOR pathway. Rather, it associates with the autophagy-promoting Vps34-Vps15-Beclin 1-Atg14L complex and facilitates the generation of cellular PtdIns(3)P. Our results unveil a previously unknown function for p110-β as a positive regulator of autophagy in multicellular organisms.