NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity.
The Beclin 1-Vps34 complex, the core component of the class III phosphatidylinositol-3 kinase (PI3K-III), binds Atg14L or UVRAG to control different steps of autophagy. However, the mechanism underlying the control of PI3K-III activity remains elusive. Here we report the identification of NRBF2 as a component in the specific PI3K-III complex and a modulator of PI3K-III activity. Through its microtubule interaction and trafficking (MIT) domain, NRBF2 binds Atg14L directly and enhances Atg14L-linked Vps34 kinase activity and autophagy induction. NRBF2-deficient cells exhibit enhanced vulnerability to endoplasmic reticulum (ER) stress that is reversed by re-introducing exogenous NRBF2. NRBF2-deficient mice develop focal liver necrosis and ductular reaction, accompanied by impaired Atg14L-linked Vps34 activity and autophagy, although the mice show no increased mortality. Our data reveal a key role for NRBF2 in the assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction. Thus, NRBF2 modulates autophagy via regulation of PI3K-III and prevents ER stress-mediated cytotoxicity and liver injury.
1] Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA [2] School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China [3].
Jiahong
J
Lu
1] Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA [2].
Liqiang
L
He
Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt, Germany.
Christian
C
Behrends
Division of Bioinformatics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
Masatake
M
Araki
Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
Kimi
K
Araki
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
Qing
Q
Jun Wang
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, New York, USA.
Joseph M
JM
Catanzaro
Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Scott L
SL
Friedman
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, New York, USA.
Wei-Xing
WX
Zong
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
M Isabel
MI
Fiel
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
Min
M
Li
Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Zhenyu
Z
Yue
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D015153:Blotting, Western; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D055785:Gene Knockdown Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018345:Mice, Knockout; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009336:Necrosis; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D015534:Trans-Activators; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C561107:Atg14 protein, mouse; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C504658:Nrbf2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D019284:Thapsigargin; D058546:Class III Phosphatidylinositol 3-Kinases; D004121:Dimethyl Sulfoxide