Epidermal stratification requires retromer-mediated desmoglein-1 recycling

Marihan Hegazy, Jennifer L. Koetsier, Amber L. Huffine, Joshua Allen Broussard, Brendan M. Godsel, Eran Cohen-Barak, Eli Sprecher, Donald J. Wolfgeher, Stephen J. Kron, Lisa M. Godsel*, Kathleen Janee Green*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly understood. Here, we identify an interaction between the retromer endosomal trafficking component, VPS35, and the desmosomal cadherin, desmoglein-1 (Dsg1). Dsg1 is specifically expressed in stratified epidermis and, when properly localized on the plasma membrane of basal keratinocytes, promotes stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support human keratinocyte stratification. The retromer-enhancing chaperone, R55, promotes the membrane localization of Dsg1 and a trafficking-deficient mutant associated with a severe inflammatory skin disorder, enhancing its ability to promote stratification. In the absence of Dsg1, retromer association with and expression of the glucose transporter GLUT1 increases, exposing a potential link between Dsg1 deficiency and epidermal metabolism. Our work provides evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)2683-2698.e8
JournalDevelopmental Cell
Volume57
Issue number24
DOIs
StatePublished - Dec 19 2022

Keywords

  • cadherin
  • desmosome
  • Dsg1
  • endosomal trafficking
  • epidermal differentiation
  • GLUT1
  • keratinocyte
  • retromer chaperone
  • SAM syndrome
  • VPS35

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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