Keratinocyte desmoglein 1 regulates the epidermal microenvironment and tanning response

Abstract

34Coordinated responses to environmental stimuli within the keratinocyte:melanocyte niche are poorly 35 understood. Desmoglein 1 (Dsg1), a keratinocyte-specific desmosomal cell-cell adhesion protein with 36 emerging signaling roles, is reduced by ultraviolet light radiation. Loss-of-function Dsg1 mutations 37 elevate keratinocyte cytokines in Severe dermatitis, multiple Allergies, and Metabolic wasting (SAM) 38 syndrome. We asked whether Dsg1 regulates keratinocyte:melanocyte paracrine communication to 39 induce the tanning response. Dsg1-silenced keratinocytes increased Pro-opiomelanocortin mRNA 40 and cytokine secretion. Melanocytes treated with conditioned media from Dsg1-silenced 41 keratinocytes exhibited increased Mitf and Trp1 mRNA, melanin secretion, and dendrite length. 42Inhibiting the melanocyte pigment-associated melanocortin 1 receptor reduced pigment secretion in 43 response to Dsg1-deficient conditioned media. Melanocytes incorporated into Dsg1-deficient human 44 skin equivalents relocalized suprabasally, reminiscent of early melanoma pagetoid behavior. Dsg1 45 decreased in keratinocytes surrounding dysplastic nevi and early melanoma, but not benign nevi. We 46 posit Dsg1 controls keratinocyte:melanocyte communication through paracrine signaling, which goes 47 57