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Epidermal Stratification Requires Retromer-Mediated Desmoglein-1 Recycling

47 Pages Posted: 22 Nov 2021 Publication Status: Published

See all articles by Marihan Hegazy

Marihan Hegazy

Northwestern University - Department of Pathology

Jennifer L. Koetsier

Northwestern University - Department of Pathology

Amber L. Huffine

Northwestern University - Department of Pathology

Joshua Allen Broussard

Northwestern University - Department of Pathology

Brendan M. Godsel

Northwestern University - Department of Pathology

Lisa M. Godsel

Northwestern University - Department of Pathology

Kathleen J. Green

Northwestern University - Department of Pathology

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Abstract

Sorting and trafficking transmembrane cargo is essential for tissue development and homeostasis. However, the importance of intracellular trafficking in the development and regeneration of stratified epidermis is not well understood. Here we identify an interaction between VPS35, an essential component of the retromer endosomal trafficking complex, and the desmosomal cadherin, Desmoglein 1 (Dsg1). Dsg1 is specifically expressed in stratified tissues and when properly localized on the plasma membrane, promotes epidermal stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support keratinocyte stratification and differentiation. The retromer enhancing chaperone, R55, promotes the plasma membrane localization of Dsg1 and a trafficking-deficient mutant associated with Severe dermatitis, multiple Allergies, and Metabolic wasting (SAM) syndrome enhancing the ability of SAM-Dsg1 to promote stratification. Our work provides the first evidence for retromer function in epidermal regeneration and identifies it as a potential therapeutic skin disease target.

Keywords: desmosome, keratinocyte, epidermal differentiation, skin disease, endosomal trafficking, retromer chaperone, VPS35, SAM syndrome, cadherin, Dsg1

Suggested Citation

Hegazy, Marihan and Koetsier, Jennifer L. and Huffine, Amber L. and Broussard, Joshua Allen and Godsel, Brendan M. and Godsel, Lisa M. and Green, Kathleen J., Epidermal Stratification Requires Retromer-Mediated Desmoglein-1 Recycling. Available at SSRN: https://ssrn.com/abstract=3969390 or http://dx.doi.org/10.2139/ssrn.3969390
This version of the paper has not been formally peer reviewed.

Marihan Hegazy

Northwestern University - Department of Pathology ( email )

Chicago, IL
United States

Jennifer L. Koetsier

Northwestern University - Department of Pathology ( email )

Chicago, IL
United States

Amber L. Huffine

Northwestern University - Department of Pathology ( email )

Chicago, IL
United States

Joshua Allen Broussard

Northwestern University - Department of Pathology

Chicago, IL
United States

Brendan M. Godsel

Northwestern University - Department of Pathology ( email )

Chicago, IL
United States

Lisa M. Godsel

Northwestern University - Department of Pathology ( email )

Chicago, IL
United States

Kathleen J. Green (Contact Author)

Northwestern University - Department of Pathology ( email )

Chicago, IL
United States

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