PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex

Nat Cell Biol. 2013 Oct;15(10):1206-1219. doi: 10.1038/ncb2848. Epub 2013 Sep 22.

Abstract

Endoplasmic reticulum (ER)-Golgi membrane transport and autophagy are intersecting trafficking pathways that are tightly regulated and crucial for homeostasis, development and disease. Here, we identify UVRAG, a beclin-1-binding autophagic factor, as a phosphatidylinositol-3-phosphate (PtdIns(3)P)-binding protein that depends on PtdIns(3)P for its ER localization. We further show that UVRAG interacts with RINT-1, and acts as an integral component of the RINT-1-containing ER tethering complex, which couples phosphoinositide metabolism to COPI-vesicle tethering. Displacement or knockdown of UVRAG profoundly disrupted COPI cargo transfer to the ER and Golgi integrity. Intriguingly, autophagy caused the dissociation of UVRAG from the ER tether, which in turn worked in concert with the Bif-1-beclin-1-PI(3)KC3 complex to mobilize Atg9 translocation for autophagosome formation. These findings identify a regulatory mechanism that coordinates Golgi-ER retrograde and autophagy-related vesicular trafficking events through physical and functional interactions between UVRAG, phosphoinositide and their regulatory factors, thereby ensuring spatiotemporal fidelity of membrane trafficking and maintenance of organelle homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy
  • Autophagy-Related Proteins
  • Beclin-1
  • Biological Transport
  • COS Cells
  • Cell Line
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism*
  • Golgi Apparatus / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Proteins / metabolism*
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphatidylinositols / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Tumor Suppressor Proteins / metabolism*
  • Vesicular Transport Proteins

Substances

  • Apoptosis Regulatory Proteins
  • Atg9a protein, human
  • Autophagy-Related Proteins
  • BECN1 protein, human
  • Beclin-1
  • Membrane Proteins
  • Phosphatidylinositols
  • Tumor Suppressor Proteins
  • UVRAG protein, human
  • Vesicular Transport Proteins