The Desmosomal Protein Desmoglein 1 Aids Recovery of Epidermal Differentiation after Acute UV Light Exposure

Abstract

Epidermal structure is damaged by exposure to ultraviolet (UV) light but the molecular mechanisms governing structural repair are largely unknown. UVB (290-320 nm wavelengths) exposure prior to induction of differentiation reduced expression of differentiation-associated proteins, including Desmoglein 1 (Dsg1), Desmocollin 1 (Dsc1) and Keratins 1 and 10 (K1/K10) in a dose-dependent manner in normal human epidermal keratinocytes (NHEKs). The UVB- induced reduction in both Dsg1 transcript and protein was associated with reduced binding of the p63 transcription factor to previously unreported enhancer regulatory regions of the Dsg1 gene. Since Dsg1 promotes epidermal differentiation in addition to participating in cell-cell adhesion, the role of Dsg1 in aiding differentiation after UVB damage was tested. Compared to controls, depleting Dsg1 via shRNA resulted in further reduction of Dsc1 and K1/K10 expression in monolayer NHEK cultures and in abnormal epidermal architecture in organotypic skin models recovering from UVB exposure. Ectopic expression of Dsg1 in keratinocyte monolayers rescued the UVB-induced differentiation defect. Treatment of UVB-exposed monolayer or organotypic cultures with Trichostatin A, a histone deacetylase inhibitor, partially restored differentiation marker expression, suggesting a potential therapeutic strategy for reversing UV-induced impairment of epidermal differentiation after acute sun exposure.

Epidermal cell junctions and their regulation by p63 in health and disease

“…These desmosomal components are also downregulated in human keratinocytes derived from AEC patients and focal downregulation of DSP and DSC3 expression is observed in non-lesional skin of AEC patients (Ferone et al 2013;Koster et al 2014), confirming their possible causative role in the pathogenesis of AEC syndrome. In agreement with a dominant negative function of AEC mutation, Dsp, Dsc3 and Dsg1 are also downregulated in p63-depleted keratinocytes and are shown to be direct p63 target genes by luciferase (Luc) assay and ChIP experiments (Ferone et al 2013;Johnson et al 2014). A dramatic reduction in Dsg1 expression was similarly reported in ΔNp63 GFP/GFP mice (Romano et al 2012), while Dsp and Dsc3 were not tested.…”

Desmosomes: Regulators of Cellular Signaling and Adhesion in Epidermal Health and Disease

“…It has long been known that PKC signaling regulates expression of desmosomal cadherins in keratinocytes (Denning et al 1998). Suppression of PKC-a or PKC-d isoforms increases Dsg3 expression, whereas suppression of PKC-d and PKC-1 isoforms either decreases or increases Dsg1 levels, respectively (Szegedi et al 2009 (Roemer 2012) and p63 has been shown by chromatin immunoprecipitation (ChIP) to bind and activate Dsg1, Dsc3, and Dp promoters (Ferone et al 2013;Johnson et al 2014). Rho-mediated changes in the actin cytoskeleton lead to changes in Srf-dependent transcription (Miralles et al 2003) and Srf controls the expression of Pkp2 and Dsg1, which in turn drives a program of terminal differentiation (Leitner et al 2011;Dubash et al 2013), The Wnt-regulated TCF/Lef transcription complex has been implicated in regulation of Dsg4, Dsc2, Dsc3, and Pg expression but direct binding of these transcription factors to desmosomal component promoters has only been shown in a few instances (Table 1) (Bazzi et al 2009;Bailey et al 2012;Tokonzaba et al 2013).…”

“…In line with these findings, Dsg1 and Dsc1 are reduced by UVB (290-to 320-nm wavelengths) exposure in keratinocytes beginning to differentiate. Importantly, ectopic Dsg1 expression counteracts UVB-induced loss of differentiation markers (Johnson et al 2014) indicating that desmosomal components contribute directly to epidermal responses to carcinogenic exposure.…”

“…Other drugs that increase desmosomal protein expression and strengthen desmosomes may lead to reduced symptoms arising from desmosomal diseases, reduced epidermal damage after environmental exposure, and prevention of carcinogenesis. These include EGFR inhibitors, histone deacetylase inhibitors, cholinergic agonists, or tyrosine phosphatase inhibitors like sodium pervanadate (Nguyen et al 2003;Lorch et al 2004;Garrod et al 2008;Simpson et al 2010;Aktary and Pasdar 2012;Johnson et al 2014).…”

150th Anniversary Series: Desmosomes and the Hallmarks of Cancer

“…Recent years identified a number of transcriptional factors that modulate 4 O. HUBER & I. PETERSEN desmosomal cadherin expression including Stat6, Klf5, Smad4, grainy head-like 1, Foxn1, Cdx1/Cdx2, c-Rel, lymphocyte enhancer factor/transcription factor (LEF/ TCF), and p53/p63 (Ferone et al, 2013;Funakoshi et al, 2008;Johnson et al, 2014;Kenchegowda et al, 2012;Mlacki et al, 2014;Omori-Miyake et al, 2014;Oshiro et al, 2003;Owens et al, 2008;Tokonzaba et al, 2013;Wilanowski et al, 2008). Interestingly, plakoglobin in a complex with LEF-1 is able to bind to the proximal promoter regions of both Dsc2 and Dsc3, however with opposite effects.…”