The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome

Eran Cohen-Barak; Lisa M. Godsel; Jennifer L. Koetsier; Marihan Hegazy; Daniella Kushnir-Grinbaum; Helwe Hammad; Nada Danial-Farran; Robert Harmon; Morad Khayat; Ron Bochner; Alon Peled; Mati Rozenblat; Judit Krausz; Ofer Sarig; Jodi L. Johnson; Michael Ziv; Stavit A. Shalev; Eli Sprecher; Kathleen J. Green

doi:10.1016/j.jid.2019.08.433

The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome

Eran Cohen-Barak, Lisa M. Godsel, Jennifer L. Koetsier, Marihan Hegazy, Daniella Kushnir-Grinbaum, Helwe Hammad, Nada Danial-Farran, Robert Harmon, Morad Khayat, Ron Bochner, Alon Peled, Mati Rozenblat, Judit Krausz, Ofer Sarig, Jodi L. Johnson, Michael Ziv, Stavit A. Shalev, Eli Sprecher, Kathleen J. Green^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	556-567.e9
Journal	Journal of Investigative Dermatology
Volume	140
Issue number	3
DOIs	https://doi.org/10.1016/j.jid.2019.08.433
State	Published - Mar 2020

Funding

This work was supported by the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR041836 and National Institutes of Health R37 AR43380 to KJG, and by a Fulbright postdoctoral fellowship grant to ECB. MH was supported by the National Institutes of Health T32 Training Grant (T32 CA009560). Additional support was provided by the JL Mayberry endowment to KJG. We acknowledge support and materials from the Northwestern University Skin Biology and Diseases Resource-Based Center supported by 5P30AR057216. We thank Chen Gafni and Efrat Mamluk from “Emek” Medical Center for their assistance. Conceptualization: ECB, KJG, ES; Data Curation: ECB, LMG, JLJ; Formal Analysis: ECB, MH; Funding Acquisition: ECB, MZ, KJG; Investigation: ECB; Methodology: ECB, LMG, KJG; Project Administration: KJG; Resources: JLK, DKG, HH, NFD, MK, MR, JK, RH, RB, AP, MH, OS, MZ, SAS, ES; Software: ECB; Supervision: LMG, KJG; Validation: LMG, KJG; Visualization: LMG, KJG, JLJ; Writing - Original Draft Preparation: ECB, JLJ; Writing - Review and Editing: JLJ, LMG, KJG. This work was supported by the National Institutes of Health / National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR041836 and National Institutes of Health R37 AR43380 to KJG, and by a Fulbright postdoctoral fellowship grant to ECB . MH was supported by the National Institutes of Health T32 Training Grant ( T32 CA009560 ). Additional support was provided by the JL Mayberry endowment to KJG. We acknowledge support and materials from the Northwestern University Skin Biology and Diseases Resource-Based Center supported by 5P30AR057216 . We thank Chen Gafni and Efrat Mamluk from “Emek” Medical Center for their assistance.

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Dermatology
Cell Biology

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Cohen-Barak, E., Godsel, L. M., Koetsier, J. L., Hegazy, M., Kushnir-Grinbaum, D., Hammad, H., Danial-Farran, N., Harmon, R., Khayat, M., Bochner, R., Peled, A., Rozenblat, M., Krausz, J., Sarig, O., Johnson, J. L., Ziv, M., Shalev, S. A., Sprecher, E., & Green, K. J. (2020). The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome. Journal of Investigative Dermatology, 140(3), 556-567.e9. https://doi.org/10.1016/j.jid.2019.08.433

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title = "The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome",

abstract = "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.",

author = "Eran Cohen-Barak and Godsel, {Lisa M.} and Koetsier, {Jennifer L.} and Marihan Hegazy and Daniella Kushnir-Grinbaum and Helwe Hammad and Nada Danial-Farran and Robert Harmon and Morad Khayat and Ron Bochner and Alon Peled and Mati Rozenblat and Judit Krausz and Ofer Sarig and Johnson, {Jodi L.} and Michael Ziv and Shalev, {Stavit A.} and Eli Sprecher and Green, {Kathleen J.}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2020",

month = mar,

doi = "10.1016/j.jid.2019.08.433",

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Cohen-Barak, E, Godsel, LM, Koetsier, JL, Hegazy, M, Kushnir-Grinbaum, D, Hammad, H, Danial-Farran, N, Harmon, R, Khayat, M, Bochner, R, Peled, A, Rozenblat, M, Krausz, J, Sarig, O, Johnson, JL, Ziv, M, Shalev, SA, Sprecher, E & Green, KJ 2020, 'The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome', Journal of Investigative Dermatology, vol. 140, no. 3, pp. 556-567.e9. https://doi.org/10.1016/j.jid.2019.08.433

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T1 - The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome

AU - Cohen-Barak, Eran

AU - Godsel, Lisa M.

AU - Koetsier, Jennifer L.

AU - Hegazy, Marihan

AU - Kushnir-Grinbaum, Daniella

AU - Hammad, Helwe

AU - Danial-Farran, Nada

AU - Harmon, Robert

AU - Khayat, Morad

AU - Bochner, Ron

AU - Peled, Alon

AU - Rozenblat, Mati

AU - Krausz, Judit

AU - Sarig, Ofer

AU - Johnson, Jodi L.

AU - Ziv, Michael

AU - Shalev, Stavit A.

AU - Sprecher, Eli

AU - Green, Kathleen J.

PY - 2020/3

Y1 - 2020/3

N2 - 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.

AB - 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.

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The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome

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