Vps35-deficiency impairs SLC4A11 trafficking and promotes corneal dystrophy

PLoS One. 2017 Sep 21;12(9):e0184906. doi: 10.1371/journal.pone.0184906. eCollection 2017.

Abstract

Vps35 (vacuolar protein sorting 35) is a major component of retromer that selectively promotes endosome-to-Golgi retrieval of transmembrane proteins. Dysfunction of retromer is a risk factor for the pathogenesis of Parkinson's disease (PD) and Alzheimer's disease (AD). However, Vps35/retromer's function in the eye or the contribution of Vps35-deficiency to eye degenerative disorders remains to be explored. Here we provide evidence for a critical role of Vps35 in mouse corneal dystrophy. Vps35 is expressed in mouse and human cornea. Mouse cornea from Vps35 heterozygotes (Vps35+/-) show features of dystrophy, such as loss of both endothelial and epithelial cell densities, disorganizations of endothelial, stroma, and epithelial cells, excrescences in the Descemet membrane, and corneal edema. Additionally, corneal epithelial cell proliferation was reduced in Vps35-deficient mice. Intriguingly, cell surface targeting of SLC4A11, a membrane transport protein (OH- /H+ /NH3 /H2O) of corneal endothelium, whose mutations have been identified in patients with corneal dystrophy, was impaired in Vps35-deficient cells and cornea. Taken together, these results suggest that SLC4A11 appears to be a Vps35/retromer cargo, and Vps35-regulation of SLC4A11 trafficking may underlie Vps35/retromer regulation of corneal dystrophy.

MeSH terms

  • Animals
  • Anion Transport Proteins / metabolism*
  • Biological Transport, Active / physiology*
  • Blotting, Western
  • Cell Proliferation / physiology
  • Cornea / metabolism*
  • Cornea / pathology
  • Corneal Dystrophies, Hereditary / metabolism*
  • Corneal Dystrophies, Hereditary / pathology
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Fluorescent Antibody Technique
  • HEK293 Cells
  • Humans
  • Mice, Transgenic
  • Microscopy, Confocal
  • Retina / metabolism
  • Retina / pathology
  • Symporters / metabolism*
  • Transfection
  • Vesicular Transport Proteins / deficiency*
  • Vesicular Transport Proteins / genetics

Substances

  • Anion Transport Proteins
  • Slc4a11 protein, mouse
  • Symporters
  • Vesicular Transport Proteins
  • Vps35 protein, mouse