Cytoplasmic control of Rab family small GTPases through BAG6

EMBO Rep. 2019 Apr;20(4):e46794. doi: 10.15252/embr.201846794. Epub 2019 Feb 25.


Rab family small GTPases are master regulators of distinct steps of intracellular vesicle trafficking in eukaryotic cells. GDP-bound cytoplasmic forms of Rab proteins are prone to aggregation due to the exposure of hydrophobic groups but the machinery that determines the fate of Rab species in the cytosol has not been elucidated in detail. In this study, we find that BAG6 (BAT3/Scythe) predominantly recognizes a cryptic portion of GDP-associated Rab8a, while its major GTP-bound active form is not recognized. The hydrophobic residues of the Switch I region of Rab8a are essential for its interaction with BAG6 and the degradation of GDP-Rab8a via the ubiquitin-proteasome system. BAG6 prevents the excess accumulation of inactive Rab8a, whose accumulation impairs intracellular membrane trafficking. BAG6 binds not only Rab8a but also a functionally distinct set of Rab family proteins, and is also required for the correct distribution of Golgi and endosomal markers. From these observations, we suggest that Rab proteins represent a novel set of substrates for BAG6, and the BAG6-mediated pathway is associated with the regulation of membrane vesicle trafficking events in mammalian cells.

Keywords: BAG6; Rab GTP‐binding proteins; Rab8a; membrane trafficking; ubiquitin‐proteasome system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cell Membrane / metabolism
  • Cytoplasm / metabolism
  • Cytosol / metabolism
  • Endoplasmic Reticulum / metabolism
  • Endosomes / metabolism
  • Gene Deletion
  • Golgi Apparatus / metabolism
  • Humans
  • Models, Biological
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • Proteolysis
  • RNA, Small Interfering / genetics
  • Ubiquitin / metabolism
  • rab GTP-Binding Proteins / chemistry
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*


  • BAG6 protein, human
  • Molecular Chaperones
  • RNA, Small Interfering
  • Ubiquitin
  • RAB8A protein, human
  • rab GTP-Binding Proteins