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

Author

Listed:
  • Jiahong Lu

    (Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
    School of Chinese Medicine, Hong Kong Baptist University)

  • 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)

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.

Suggested Citation

  • 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, 2014. "NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity," Nature Communications, Nature, vol. 5(1), pages 1-15, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4920
    DOI: 10.1038/ncomms4920
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