ATP6AP2 functions as a V-ATPase assembly factor in the endoplasmic reticulum

Mol Biol Cell. 2018 Sep 1;29(18):2156-2164. doi: 10.1091/mbc.E18-04-0234. Epub 2018 Jul 11.


ATP6AP2 (also known as the [pro]renin receptor) is a type I transmembrane protein that can be cleaved into two fragments in the Golgi apparatus. While in Drosophila ATP6AP2 functions in the planar cell polarity (PCP) pathway, recent human genetic studies have suggested that ATP6AP2 could participate in the assembly of the V-ATPase in the endoplasmic reticulum (ER). Using a yeast model, we show here that the V-ATPase assembly factor Voa1 can functionally be replaced by Drosophila ATP6AP2. This rescue is even more efficient when coexpressing its binding partner ATP6AP1, indicating that these two proteins together fulfill Voa1 functions in higher organisms. Structure-function analyses in both yeast and Drosophila show that proteolytic cleavage is dispensable, while C-terminus-dependent ER retrieval is required for ATP6AP2 function. Accordingly, we demonstrate that both overexpression and lack of ATP6AP2 causes ER stress in Drosophila wing cells and that the induction of ER stress is sufficient to cause PCP phenotypes. In summary, our results suggest that full-length ATP6AP2 contributes to the assembly of the V-ATPase proton pore and that impairment of this function affects ER homeostasis and PCP signaling.

Publication types

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

MeSH terms

  • Animals
  • Cell Polarity / physiology
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / enzymology
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress
  • Golgi Apparatus / metabolism
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism*


  • ATP6AP2 protein, Drosophila
  • ATP6AP2 protein, human
  • Drosophila Proteins
  • Membrane Proteins
  • Receptors, Cell Surface
  • Saccharomyces cerevisiae Proteins
  • VOA1 protein, S cerevisiae
  • Vacuolar Proton-Translocating ATPases