NRBF2 Regulates Autophagy and Prevents Liver Injury by Modulating Atg14L-Linked Phosphatidylinositol-3 Kinase III Activity

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.

Document Type

Article

Publication Date

5-22-2014

Notes/Citation Information

Published in Nature Communications, v. 5, article 3920, p. 1-15.

Digital Object Identifier (DOI)

http://dx.doi.org/10.1038/ncomms4920

Funding Information

This work was supported by National Institutes of Health grants (NIH-R01NS060123) to Z.Y.

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