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Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes
- Source :
- The Journal of Cell Biology, The Journal of Experimental Medicine
- Publication Year :
- 2016
- Publisher :
- Rockefeller University Press, 2016.
-
Abstract
- Loss of the desmosome armadillo protein Plakophilin-2 in neonatal cardiomyocytes results in decreased stability and expression of the cytoskeletal linker protein Desmoplakin, which causes activation of a TGF-β1/p38 MAPK signaling cascade and induces expression of fibrotic genes.<br />Members of the desmosome protein family are integral components of the cardiac area composita, a mixed junctional complex responsible for electromechanical coupling between cardiomyocytes. In this study, we provide evidence that loss of the desmosomal armadillo protein Plakophilin-2 (PKP2) in cardiomyocytes elevates transforming growth factor β1 (TGF-β1) and p38 mitogen-activated protein kinase (MAPK) signaling, which together coordinate a transcriptional program that results in increased expression of profibrotic genes. Importantly, we demonstrate that expression of Desmoplakin (DP) is lost upon PKP2 knockdown and that restoration of DP expression rescues the activation of this TGF-β1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-β1/p38 MAPK signaling and induction of fibrotic gene expression in vivo. These data therefore identify PKP2 and DP as central players in coordination of desmosome-dependent TGF-β1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Time Factors
Transcription, Genetic
p38 Mitogen-Activated Protein Kinases
Rats, Sprague-Dawley
Mice
0302 clinical medicine
Desmosome
Conditional gene knockout
Immunology and Allergy
Myocytes, Cardiac
Phosphorylation
Research Articles
Regulation of gene expression
Genetics
Mice, Knockout
Gene knockdown
0303 health sciences
biology
integumentary system
Protein Stability
Cell biology
medicine.anatomical_structure
Phenotype
RNA Interference
Signal transduction
Inflammation Mediators
Cardiomyopathies
Signal Transduction
Genotype
Immunology
Transfection
Article
Cell Line
Transforming Growth Factor beta1
03 medical and health sciences
medicine
Animals
Protein kinase A
Of Interest
030304 developmental biology
Desmoplakin
From the JCB
Cell Biology
Fibrosis
Enzyme Activation
030104 developmental biology
Animals, Newborn
Desmoplakins
Gene Expression Regulation
biology.protein
Plakophilins
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15409538 and 00221007
- Volume :
- 213
- Database :
- OpenAIRE
- Journal :
- The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....5074401ccb4689316882a74045b3afd4
- Full Text :
- https://doi.org/10.1084/jem.2133oia12