Investigators have identified a novel role for an intracellular trafficking pathway in regulating epidermal developmental processes, which could serve as a future therapeutic target for inflammatory skin diseases, according to a Northwestern Medicine study published in Developmental Cell.
The epidermis, the skin’s outermost layer, is a regenerating multi-layered tissue that relies on the proper sorting of basal cells to replenish the upper layers of the tissue for skin development and maintenance. However, the intracellular trafficking mechanisms that regulate this process have remained elusive.
“Changes in protein trafficking have been observed in a number of diseases, but the importance of specific trafficking mechanisms in the pathogenesis of epidermal diseases is not well understood,” said Kathleen Green, PhD, the Joseph L. Mayberry, Sr., Professor of Pathology and Toxicology and associate director for Basic Science Research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and co-senior author of the study.
Recent work from the Green laboratory also found that the cadherin desmoglein-1 (Dsg1), a cellular adhesion molecule, is downregulated in many inflammatory skin diseases. This discovery prompted Green’s team to investigate Dsg1 trafficking mechanisms and whether increasing Dsg1 localization on the cell surface by enhancing the activity of the trafficking pathways it utilizes could be a viable approach for treating inflammatory skin disorders.
Using biochemical and immunofluorescence approaches to analyze genetically modified epidermal cells, the investigators uncovered a novel intracellular interaction between VPS35, a component of the endosomal trafficking complex called the retromer, and Dsg1, which is exclusively expressed in multi-layered epithelial tissues.
By studying both in vitro and in vivo models of the epidermis, they also discovered that a small molecule “chaperone” drug called R55 (which has been tested in preclinical models of Alzheimer’s and ALS) increases the plasma membrane localization and function of wild type Dsg1 and a disease-associated Dsg1 variant, which causes the rare disease known as severe skin dermatitis, multiple allergies and metabolic wasting (SAM) syndrome. The R55 compound works to increase retromer function by stabilizing the trafficking complex.
Furthermore, enhanced localization of Dsg1 on the plasma membrane of basal cells promoted epithelial stratification, or the layering of epithelial cells, and epithelial cell differentiation.
“We suggest that retromer chaperones like R55 might be a way to increase Dsg1 in different skin diseases that are associated with a loss in Dsg1, such as psoriasis as SAM syndrome,” said Marihan Hegazy, a student in the Driskill Graduate Program in Life Sciences (DGP) and lead author of the study.
The current findings are the first to demonstrate a direct link between retromer function and epidermal regeneration and point to the retromer as a potential therapeutic target.
“This small molecule can improve the localization of mutant Dsg1 and improve its function by getting it to where it’s supposed to be. If it does that with a rare disease mutation, maybe it would work in other more common skin diseases that exhibit a loss of Dsg1,” said Green, who is also a professor of Dermatology.
The authors noted that in future studies, their team aims to test an updated version of the small molecule drug which has been shown to be less toxic and potentially more effective in preclinical models.
This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01 AR041836, R01 AR043380, F31 AR076188, K01 AR075087 and T32 AR060710, National Cancer Institute grants R01 CA228196 and T32 CA009560, and partial support from J.L. Mayberry Endowment.