Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal degradation of connexin-43

Kam, Chen Yuan; Dubash, Adi D.; Magistrati, Elisa; Polo, Simona; Satchell, K.J.F.; Sheikh, Farah; Lampe, Paul D.; Green, Kathleen J.

doi:10.1083/jcb.201710161

Cited by 51 publications

(44 citation statements)

References 92 publications

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“…Thus, impaired cadherin binding by Trp excess or disturbed desmosomal function by reduced DSG2 or PG levels were interrupting proper electrical conduction with induction of arrhythmia. These data are in line with studies demonstrating that deficiency or mutation of desmosomal proteins can result in impaired GJ protein expression, localization and disrupted conduction of excitation . In addition, the function of the β 1 ‐adrenergic receptor inducing downstream signalling via cAMP was disturbed by impaired desmosomal composition or blocked cadherin binding.…”

Section: Discussionsupporting

confidence: 89%

“…These data are in line with studies demonstrating that deficiency or mutation of desmosomal proteins can result in impaired GJ protein expression, localization and disrupted conduction of excitation. [27][28][29][30][31][32][33] In addition, the function of the β 1 -adrenergic receptor inducing downstream signalling via cAMP was disturbed by impaired desmosomal composition or blocked cadherin binding. This revealed, to our knowledge for the first time, the dependency of sufficient β 1adrenergic receptor function on proper desmosomal cohesion.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

et al. 2019

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Aims Mutations in desmosomal proteins can induce arrhythmogenic cardiomyopathy with life‐threatening arrhythmia. Previous data demonstrated adrenergic signalling to be important to regulate desmosomal cohesion in cardiac myocytes. Here, we investigated how signalling pathways including adrenergic signalling, PKC and SERCA regulate desmosomal adhesion and how this controls gap junctions (GJs) in cardiac myocytes. Methods Immunostaining, Western blot, dissociation assay and multi‐electrode array were applied in HL‐1 cardiac myocytes to evaluate localization, expression and function of desmosomal and GJ components. cAMP levels were determined by ELISA. Results Activation of PKC by PMA or adrenergic signalling increased cell cohesion and desmoglein‐2 and desmoplakin localization at cell‐cell junctions, whereas tryptophan (Trp) treatment to inhibit cadherin binding or inhibition of SERCA by thapsigargin reduced cell cohesion, while cAMP elevation rescued this effect. Despite no changes in protein expression, accumulation of GJ protein connexin‐43 was detectable at cell‐cell contacts in parallel to increased cohesion. Disruption of cell cohesion by Trp, PMA or thapsigargin impaired conduction of excitation comparable to GJ inhibition. cAMP elevation was effective to improve arrhythmia after Trp treatment. Weakened cell cohesion by Trp or depletion of desmoglein‐2 or plakoglobin blocked signalling via the β1‐adrenergic receptor. Moreover, silencing of desmosomal proteins increased arrhythmia and reduced conduction velocity, which were rescued by cAMP elevation. Conclusion These data demonstrate the interplay of GJs, desmosomes and the β1‐adrenergic receptor with regulation of their function by cell cohesion, adrenergic and PKC signalling or SERCA inhibition. These results support the identification of new targets to treat arrhythmogenic cardiomyopathy.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

et al. 2019

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“…Recently, Green and colleagues demonstrated that Cx43 ubiquitination is involved in modulating gap junction levels in cardiac cells in response to loss of desmoplakin, a key component of desmosomes [138]. Desmosomes are cadherin-based intercellular adhesive junctions that have important roles in maintaining the integrity of the myocardium by tethering the intermediate filament cytoskeleton to sites of cell-cell adhesion [139].…”

Section: Role Of Connexin Ubiquitination In the Regulation Of Gap Junmentioning

confidence: 99%

“…Conditional knock-out of desmoplakin in mouse cardiac cells results in a significant reduction in Cx43 protein levels [140,141]. Mechanistically, loss of desmoplakin causes activation of the ERK1/2-MAPK pathway, which then stimulates phosphorylation of Ser279 and Ser282 within the C-terminal tail of Cx43 [138]. In neonatal rat ventricular cardiomyocytes, this phosphorylation event was found to be associated with increased Cx43 ubiquitination and degradation in lysosomes [138].…”

Section: Role Of Connexin Ubiquitination In the Regulation Of Gap Junmentioning

confidence: 99%

Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications

Totland

Rasmussen

Knudsen

et al. 2019

Cell. Mol. Life Sci.

119

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Gap junctions consist of arrays of intercellular channels that enable adjacent cells to communicate both electrically and metabolically. Gap junctions have a wide diversity of physiological functions, playing critical roles in both excitable and non-excitable tissues. Gap junction channels are formed by integral membrane proteins called connexins. Inherited or acquired alterations in connexins are associated with numerous diseases, including heart failure, neuropathologies, deafness, skin disorders, cataracts and cancer. Gap junctions are highly dynamic structures and by modulating the turnover rate of connexins, cells can rapidly alter the number of gap junction channels at the plasma membrane in response to extracellular or intracellular cues. Increasing evidence suggests that ubiquitination has important roles in the regulation of endoplasmic reticulum-associated degradation of connexins as well as in the modulation of gap junction endocytosis and post-endocytic sorting of connexins to lysosomes. In recent years, researchers have also started to provide insights into the physiological roles of connexin ubiquitination in specific tissue types. This review provides an overview of the advances made in understanding the roles of connexin ubiquitination in the regulation of gap junction intercellular communication and discusses the emerging physiological and pathophysiological implications of these processes.

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“…Curiously, some SAM syndrome patients present with chronic circumscribed, welldemarcated, hyperkeratotic, erythematous to brownish plaques mimicking EKV (Has et al, 2015;Cheng et al, 2016;Schlipf et al, 2016;Taiber et al, 2018). Desmosomal components such as desmoglein 2, desmoplakin (DP), plakoglobin, and plakophilin 2 can regulate Cx expression, trafficking, localization, and ubiquitination, especially in cardiac tissue (Oxford et al, 2007;Asimaki et al, 2009;Asimaki et al, 2014;Gehmlich et al, 2010;Patel et al, 2014;Kam et al, 2018). Therefore, we hypothesized that Dsg1 plays a role in GJ dynamics in the skin.…”

Section: Introductionmentioning

confidence: 99%

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

Cohen‐Barak¹,

Godsel

Koetsier

et al. 2020

Journal of Investigative Dermatology

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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 ¼ 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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Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal degradation of connexin-43

Cited by 51 publications

References 92 publications

Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications

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

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