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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy* / drug effects
  • Autophagy-Related Proteins
  • Beclin-1
  • Blotting, Western
  • Class III Phosphatidylinositol 3-Kinases / metabolism*
  • Dimethyl Sulfoxide / pharmacology
  • Endoplasmic Reticulum Stress / drug effects
  • Gene Knockdown Techniques
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology*
  • Mice, Knockout
  • Models, Biological
  • NF-E2-Related Factor 2 / metabolism
  • Necrosis
  • Phagosomes / metabolism
  • Protein Binding / drug effects
  • Protein Stability / drug effects
  • Protein Structure, Tertiary
  • Proteolysis / drug effects
  • Thapsigargin / pharmacology
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*
  • Vesicular Transport Proteins / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • Atg14 protein, mouse
  • Autophagy-Related Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Nrbf2 protein, mouse
  • Transcription Factors
  • Vesicular Transport Proteins
  • Thapsigargin
  • Class III Phosphatidylinositol 3-Kinases
  • Dimethyl Sulfoxide