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

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Desmoplakin (DP) is an obligate component of desmosomes, intercellular adhesive junctions that maintain the integrity of the epidermis and myocardium. Mutations in DP can cause cardiac and cutaneous disease, including arrhythmogenic cardiomyopathy (ACM), an inherited disorder that frequently results in deadly arrhythmias. Conduction defects in ACM are linked to the remodeling and functional interference with Cx43-based gap junctions that electrically and chemically couple cells. How DP loss impairs gap junctions is poorly understood. We show that DP prevents lysosomal-mediated degradation of Cx43. DP loss triggered robust activation of ERK1/2-MAPK and increased phosphorylation of S279/282 of Cx43, which signals clathrin-mediated internalization and subsequent lysosomal degradation of Cx43. RNA sequencing revealed Ras-GTPases as candidates for the aberrant activation of ERK1/2 upon loss of DP. Using a novel Ras inhibitor, Ras/Rap1-specific peptidase (RRSP), or K-Ras knockdown, we demonstrate restoration of Cx43 in DP-deficient cardiomyocytes. Collectively, our results reveal a novel mechanism for the regulation of the Cx43 life cycle by DP in cardiocutaneous models.

Original languageEnglish (US)
Pages (from-to)3219-3235
Number of pages17
JournalJournal of Cell Biology
Volume217
Issue number9
DOIs
StatePublished - Sep 1 2018

Fingerprint

Desmoplakins
Connexin 43
Gap Junctions
Cardiomyopathies
RNA Sequence Analysis
ras Proteins
Desmosomes
Clathrin
Intercellular Junctions
Life Cycle Stages
Skin Diseases
Cardiac Myocytes
Epidermis
Adhesives
Cardiac Arrhythmias
Heart Diseases
Myocardium
Peptide Hydrolases
Phosphorylation
Mutation

ASJC Scopus subject areas

  • Cell Biology

Cite this

Kam, Chen Yuan ; Dubash, Adi D. ; Magistrati, Elisa ; Polo, Simona ; Satchell, Karla J. F. ; Sheikh, Farah ; Lampe, Paul D. ; Green, Kathleen Janee. / Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal degradation of connexin-43. In: Journal of Cell Biology. 2018 ; Vol. 217, No. 9. pp. 3219-3235.
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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, Karla J. F.; Sheikh, Farah; Lampe, Paul D.; Green, Kathleen Janee.

In: Journal of Cell Biology, Vol. 217, No. 9, 01.09.2018, p. 3219-3235.

Research output: Contribution to journalArticle

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