Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function.
A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate the physiological function of Vps34 and to determine its precise role in autophagy, we have generated Vps34(f/f) mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and a frame shift causing a deletion of 755 of the 887 amino acids of Vps34. Acute ablation of Vps34 in MEFs upon adenoviral Cre infection results in a diminishment of localized generation of phosphatidylinositol 3-phosphate and blockade of both endocytic and autophagic degradation. Starvation-induced autophagosome formation is blocked in both Vps34-null MEFs and liver. Liver-specific Albumin-Cre;Vps34(f/f) mice developed hepatomegaly and hepatic steatosis, and impaired protein turnover. Ablation of Vps34 in the heart of muscle creatine kinase-Cre;Vps34(f/f) mice led to cardiomegaly and decreased contractility. In addition, while amino acid-stimulated mTOR activation was suppressed in the absence of Vps34, the steady-state level of mTOR signaling was not affected in Vps34-null MEFs, liver, or cardiomyocytes. Taken together, our results indicate that Vps34 plays an essential role in regulating functional autophagy and is indispensable for normal liver and heart function.
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
Nadia
N
Jaber
Zhixun
Z
Dou
Juei-Suei
JS
Chen
Joseph
J
Catanzaro
Ya-Ping
YP
Jiang
Lisa M
LM
Ballou
Elzbieta
E
Selinger
Xiaosen
X
Ouyang
Richard Z
RZ
Lin
Jianhua
J
Zhang
Wei-Xing
WX
Zong
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D058546:Class III Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000378:metabolism*; D004562:Electrocardiography; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D017353:Gene Deletion; D008099:Liver / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D010588:Phagosomes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D000596:Amino Acids; D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D058546:Class III Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases