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- Title
Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy.
- Authors
Tsui, Hoyee; van Kampen, Sebastiaan Johannes; Han, Su Ji; Meraviglia, Viviana; van Ham, Willem B.; Casini, Simona; van der Kraak, Petra; Vink, Aryan; Yin, Xiaoke; Mayr, Manuel; Bossu, Alexandre; Marchal, Gerard A.; Monshouwer-Kloots, Jantine; Eding, Joep; Versteeg, Danielle; de Ruiter, Hesther; Bezstarosti, Karel; Groeneweg, Judith; Klaasen, Sjoerd J.; van Laake, Linda W.
- Abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 (PKP2). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved. Explanted hearts from patients with ACM had less PKP2 compared with healthy hearts, which correlated with reduced expression of desmosomal and adherens junction (AJ) proteins. These proteins were also disorganized in areas of fibrotic remodeling. In vitro data from human-induced pluripotent stem cell–derived cardiomyocytes and microtissues carrying the heterozygous PKP2 c.2013delC pathogenic mutation also displayed impaired contractility. Knockin mice carrying the equivalent heterozygous Pkp2 c.1755delA mutation recapitulated changes in desmosomal and AJ proteins and displayed cardiac dysfunction and fibrosis with age. Global proteomics analysis of 4-month-old heterozygous Pkp2 c.1755delA hearts indicated involvement of the ubiquitin-proteasome system (UPS) in ACM pathogenesis. Inhibition of the UPS in mutant mice increased area composita proteins and improved calcium dynamics in isolated cardiomyocytes. Additional proteomics analyses identified lysine ubiquitination sites on the desmosomal proteins, which were more ubiquitinated in mutant mice. In summary, we show that a plakophilin-2 mutation can lead to decreased desmosomal and AJ protein expression through a UPS-dependent mechanism, which preceded cardiac remodeling. These findings suggest that targeting protein degradation and improving desmosomal protein stability may be a potential therapeutic strategy for the treatment of ACM. PKPing up the rhythm: Arrhythmogenic cardiomyopathy (ACM) is a debilitating disease with clear genetic links but variable penetrance and poorly understood mechanisms. Here Tsui and colleagues analyzed heart tissue from patients with ACM along with inducible pluripotent stem cell–derived cardiomyocytes and mice carrying a plakophilin-2 (Pkp2) mutation to reveal that decreased expression of desmosomal and adherens junction proteins correlated with cardiac dysfunction and fibrosis. Proteomics data indicated involvement of the ubiquitin-proteasome system (UPS) in the degradation of these proteins, and inhibition of the UPS improved protein expression and calcium dynamics in isolated mutant cardiomyocytes. These results suggest that therapies aimed at increasing stability of desmosomal proteins may improve cardiac function in patients with ACM.--AW
- Subjects
PROTEOLYSIS; PROTEIN stability; CARDIOMYOPATHIES; ADHERENS junctions; HEART diseases; PROTEIN expression; HEART fibrosis
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 688, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.add4248