Dataset Information

Epidermal Stratification Requires Retromer-Mediated Desmoglein-1 Recycling

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 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 the first evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Keratinocyte

SUBMITTER: Donald Wolfgeher

LAB HEAD: Dr. Kathleen J. Green

PROVIDER: PXD036646 | Pride | 2023-07-24

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20170810_vcs075_17-967_Green_Brendan-Dsg1_ReRun.raw	Raw
	20170810_vcs075_17-967_Green_Brendan-Ecad.raw	Raw
	20170810_vcs075_17-967_Green_Brendan-control.raw	Raw
	220723_Green_BioID_Index.txt	Txt
	220723_Green_BioID_MQ99FDR.xml	Xml

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Publications

Epidermal stratification requires retromer-mediated desmoglein-1 recycling.

Hegazy Marihan M Koetsier Jennifer L JL Huffine Amber L AL Broussard Joshua A JA Godsel Brendan M BM Cohen-Barak Eran E Sprecher Eli E Wolfgeher Donald J DJ Kron Stephen J SJ Godsel Lisa M LM Green Kathleen J KJ

Developmental cell 20221209 24

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 retrom ...[more]

PMID: 36495876

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Project description:Epidermis, a continuously self-renewing and differentiating organ, produces a protective stratum corneum that shields us from external chemical, physical and microbial threats. Epidermal differentiation is a multi-step process regulated by influences, some unknown, others insufficiently explored. Detachment of keratinocytes from the basement membrane is one such pro-differentiation stimulus. Here, we define the transcriptional changes during differentiation, especially those caused by detachment from the substratum. Using comprehensive transcriptional profiling, we revisited the effects of detachment as a differentiation signal to keratinocytes. We identified the genes regulated by detachment, the corresponding ontological categories and, using metaanalysis, compared the genes and categories to those regulated by other pro-differentiating stimuli. We identified 762 genes overexpressed in suspended keratinocyte, including known and novel differentiation markers, and 1427 in attached cells, including basal layer markers. Detachment induced epidermis development, cornification and desmosomal genes, but also innate immunity, proliferation inhibitors, transcription regulators and MAPKs; conversely the attached cells overexpressed cell cycle, anchoring, motility, splicing and mitochondrial genes, and both positive and negative regulators of apoptosis. Metaanalysis identified which detachment-regulated categories overlap with those induced by suprabasal location in vivo, by reaching confluency in vitro, and by inhibition of JUN kinases. Attached and in vivo basal cells shared overexpression of mitochondrial components. Interestingly, melanosome trafficking components were also overexpressed in the attached and in vivo basal keratinocytes. Reaching confluency did not affect adhesion and ECM proteins. Lipid metabolism and steroid metabolism were induced by confluency and by JNK inhibition, respectively. These results suggest that specific pro-differentiation signals induce specific features of the keratinization process, which are in vivo orchestrated into harmonious epidermal homeostasis. Human epidermal keratinocytes are grown in standard growth medium either attached in tissue culture plates, or suspended, in the same medium, in bacteriological plates. After 48 hrs, attached and suspended cultures were harvested and their transcriptomes compared.