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Nat Commun. 2014 May 22;5:3920. doi: 10.1038/ncomms4920.

NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity.

Author information

1
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].
2
1] Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA [2].
3
Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt, Germany.
4
Division of Bioinformatics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
5
Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
6
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
7
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, New York, USA.
8
Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
9
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
10
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
11
Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Abstract

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.

PMID:
24849286
PMCID:
PMC4376476
DOI:
10.1038/ncomms4920
[Indexed for MEDLINE]
Free PMC Article

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