The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome.
Adolescent
Adult
Biopsy
Cell Line
Child
Child, Preschool
Connexin 43
/ metabolism
Dermatitis
/ genetics
Desmoglein 1
/ genetics
Female
Follow-Up Studies
Gap Junctions
/ metabolism
Humans
Hypersensitivity
/ genetics
Keratinocytes
Lysosomes
/ metabolism
Male
Mutation
Phosphorylation
Primary Cell Culture
Protein Kinase C
/ metabolism
Protein Stability
Proteolysis
Skin
/ immunology
Wasting Syndrome
/ genetics
Young Adult
Journal
The Journal of investigative dermatology
ISSN: 1523-1747
Titre abrégé: J Invest Dermatol
Pays: United States
ID NLM: 0426720
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
12
03
2019
revised:
15
07
2019
accepted:
02
08
2019
pubmed:
30
8
2019
medline:
11
11
2020
entrez:
30
8
2019
Statut:
ppublish
Résumé
An effective epidermal barrier requires structural and functional integration of adherens junctions, tight junctions, gap junctions (GJ), and desmosomes. Desmosomes govern epidermal integrity while GJs facilitate small molecule transfer across cell membranes. Some patients with severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, caused by biallelic desmoglein 1 (DSG1) mutations, exhibit skin lesions reminiscent of erythrokeratodermia variabilis, caused by mutations in connexin (Cx) genes. We, therefore, examined whether SAM syndrome-causing DSG1 mutations interfere with Cx expression and GJ function. Lesional skin biopsies from SAM syndrome patients (n = 7) revealed decreased Dsg1 and Cx43 plasma membrane localization compared with control and nonlesional skin. Cultured keratinocytes and organotypic skin equivalents depleted of Dsg1 exhibited reduced Cx43 expression, rescued upon re-introduction of wild-type Dsg1, but not Dsg1 constructs modeling SAM syndrome-causing mutations. Ectopic Dsg1 expression increased cell-cell dye transfer, which Cx43 silencing inhibited, suggesting that Dsg1 promotes GJ function through Cx43. As GJA1 gene expression was not decreased upon Dsg1 loss, we hypothesized that Cx43 reduction was due to enhanced protein degradation. Supporting this, PKC-dependent Cx43 S368 phosphorylation, which signals Cx43 turnover, increased after Dsg1 depletion, while lysosomal inhibition restored Cx43 levels. These data reveal a role for Dsg1 in regulating epidermal Cx43 turnover.
Identifiants
pubmed: 31465738
pii: S0022-202X(19)33151-3
doi: 10.1016/j.jid.2019.08.433
pmc: PMC7039747
mid: NIHMS1538284
pii:
doi:
Substances chimiques
Connexin 43
0
DSG1 protein, human
0
Desmoglein 1
0
GJA1 protein, human
0
Protein Kinase C
EC 2.7.11.13
Types de publication
Journal Article
Observational Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
556-567.e9Subventions
Organisme : NCI NIH HHS
ID : T32 CA009560
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR041836
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228196
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR057216
Pays : United States
Organisme : NIAMS NIH HHS
ID : R37 AR043380
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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