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

Jiahong Lu, Liqiang He, Christian Behrends, Masatake Araki, Kimi Araki, Qing Jun Wang, Joseph M. Catanzaro, Scott L. Friedman, Wei-Xing Zong, M. Isabel Fiel, Min Li and Zhenyu Yue ()
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Jiahong Lu: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Liqiang He: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Christian Behrends: Institute of Biochemistry II, Goethe University School of Medicine
Masatake Araki: Institute of Resource Development and Analysis, Kumamoto University
Kimi Araki: Institute of Resource Development and Analysis, Kumamoto University
Qing Jun Wang: College of Medicine, University of Kentucky
Joseph M. Catanzaro: Stony Brook University
Scott L. Friedman: Icahn School of Medicine at Mount Sinai
Wei-Xing Zong: Stony Brook University
M. Isabel Fiel: Icahn School of Medicine at Mount Sinai
Min Li: School of Chinese Medicine, Hong Kong Baptist University
Zhenyu Yue: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4920

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