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 language | English (US) |
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Pages (from-to) | 2683-2698.e8 |
Journal | Developmental Cell |
Volume | 57 |
Issue number | 24 |
DOIs | |
State | Published - Dec 19 2022 |
Funding
Research was supported by NIH/NIAMS P30 AR075049 awarded to Northwestern University Skin Biology & Diseases Resource-Based Center. Imaging work was performed at the Northwestern University Center for Advanced Microscopy, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 , awarded to the Robert H Lurie Comprehensive Cancer Center. Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 , awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award ( S10OD025194 ) from NIH Office of the Director , and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569 . This work was supported by NIH/NIAMS R01 AR041836 , NIH/NIAMS R01 AR043380 , and NIH/NCI R01 CA228196 with partial support from J.L. Mayberry Endowment to K.J.G. M.H. was supported by NIH/NCI T32 CA009560 and NIH/NIAMS F31 AR076188 . J.A.B. was supported by NIH/NIAMS K01 AR075087 and NIH/NIAMS T32 AR060710 .
Keywords
- Dsg1
- GLUT1
- SAM syndrome
- VPS35
- cadherin
- desmosome
- endosomal trafficking
- epidermal differentiation
- keratinocyte
- retromer chaperone
ASJC Scopus subject areas
- Molecular Biology
- General Biochemistry, Genetics and Molecular Biology
- Developmental Biology
- Cell Biology