Epidermal stratification requires retromer-mediated desmoglein-1 recycling

• Published in: Developmental cell Vol. 57; no. 24; pp. 2683 - 2698.e8
• Main Authors: Hegazy, Marihan, Koetsier, Jennifer L., Huffine, Amber L., Broussard, Joshua A., Godsel, Brendan M., Cohen-Barak, Eran, Sprecher, Eli, Wolfgeher, Donald J., Kron, Stephen J., Godsel, Lisa M., Green, Kathleen J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19-12-2022
• Subjects: cadherin; Cadherins - metabolism; Desmoglein 1 - metabolism; desmosome; Dsg1; endosomal trafficking; Endosomes - metabolism; Epidermal Cells - metabolism; epidermal differentiation; Epidermis - metabolism; GLUT1; Humans; keratinocyte; Keratinocytes - metabolism; retromer chaperone; SAM syndrome; VPS35; epidermal differentiation; SAM syndrome; GLUT1; keratinocyte; endosomal trafficking; desmosome; Dsg1; VPS35; cadherin; retromer chaperone
• DOI: 10.1016/j.devcel.2022.11.010
• EISSN: 1878-1551
• ISSN: 1534-5807

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.
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•Desmosomal cadherin, desmoglein 1, requires the retromer for endosomal trafficking•The retromer is necessary for epidermal differentiation and stratification•Retromer chaperone enhances the function of Dsg1 and a disease-associated mutant•Retromer cargo GLUT1 is upregulated in Dsg1-deficient epidermis
Hegazy et al. identify the endosomal trafficking complex, the retromer, as a regulator of epidermal development and homeostasis through its regulation of the important disease target, a desmosomal cadherin called desmoglein 1. Their work identifies the retromer as a possible therapeutic target for a systemic skin disorder.