Epidermal stratification requires retromer-mediated desmoglein-1 recycling

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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

Funding

FundersFunder number
J.L. Mayberry EndowmentT32 AR060710, T32 CA009560, K01 AR075087, F31 AR076188
National Institutes of Health
National Cancer InstituteCCSG P30 CA060553
National Institute of Arthritis and Musculoskeletal and Skin DiseasesP30AR075049
Northwestern UniversityR01 AR041836, S10OD025194, R01 CA228196, R01 AR043380, P41 GM108569, P30-CA060553

    Keywords

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

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