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, Zhenyu Yue

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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.

Original languageEnglish (US)
Article number3920
JournalNature communications
Volume5
DOIs
StatePublished - May 22 2014

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Lu, J., He, L., Behrends, C., Araki, M., Araki, K., Jun Wang, Q., Catanzaro, J. M., Friedman, S. L., Zong, W. X., Fiel, M. I., Li, M., & Yue, Z. (2014). NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity. Nature communications, 5, [3920]. https://doi.org/10.1038/ncomms4920