Rab18 and a Rab18 GEF complex are required for normal ER structure

J Cell Biol. 2014 Jun 9;205(5):707-20. doi: 10.1083/jcb.201403026. Epub 2014 Jun 2.


The ancestral Rab GTPase Rab18 and both subunits of the Rab3GAP complex are mutated in the human neurological and developmental disorder Warburg Micro syndrome. Here, we demonstrate that the Rab3GAP complex is a specific Rab18 guanine nucleotide exchange factor (GEF). The Rab3GAP complex localizes to the endoplasmic reticulum (ER) and is necessary for ER targeting of Rab18. It is also sufficient to promote membrane recruitment of Rab18. Disease-associated point mutations of conserved residues in either the Rab3GAP1 (T18P and E24V) or Rab3GAP2 (R426C) subunits result in loss of the Rab18 GEF and membrane-targeting activities. Supporting the view that Rab18 activity is important for ER structure, in the absence of either Rab3GAP subunit or Rab18 function, ER tubular networks marked by reticulon 4 were disrupted, and ER sheets defined by CLIMP-63 spread out into the cell periphery. Micro syndrome is therefore a disease characterized by direct loss of Rab18 function or loss of Rab18 activation at the ER by its GEF Rab3GAP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Endoplasmic Reticulum / metabolism*
  • GTP Phosphohydrolases / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lipids / chemistry
  • Membrane Proteins / metabolism
  • Mutation
  • Phenotype
  • Point Mutation
  • rab GTP-Binding Proteins / physiology*
  • rab3 GTP-Binding Proteins / metabolism


  • CKAP4 protein, human
  • Guanine Nucleotide Exchange Factors
  • Lipids
  • Membrane Proteins
  • RAB18 protein, human
  • RAB3GAP2 protein, human
  • GTP Phosphohydrolases
  • RAB3GAP1 protein, human
  • rab GTP-Binding Proteins
  • rab3 GTP-Binding Proteins