The class IA phosphatidylinositol 3-kinase p110-beta subunit is a positive regulator of autophagy.
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)P(3), 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.
Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
Zhixun
Z
Dou
Mohar
M
Chattopadhyay
Ji-An
JA
Pan
Jennifer L
JL
Guerriero
Ya-Ping
YP
Jiang
Lisa M
LM
Ballou
Zhenyu
Z
Yue
Richard Z
RZ
Lin
Wei-Xing
WX
Zong
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D002478:Cells, Cultured; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D057809:HEK293 Cells; D006321:Heart / Q000502:physiology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010588:Phagosomes / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
C539000:ATG14 protein, human; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D004791:Enzyme Inhibitors; D018129:Phosphatidylinositol Phosphates; D011993:Recombinant Fusion Proteins; C055525:phosphatidylinositol 3-phosphate; D058546:Class III Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt