Desmosomes: emerging pathways and non-canonical functions in cardiac arrhythmias and disease

Figures

• 

  Fig. 1. Schemata of protein degradation pathways at the cardiac desmosome. (a) In healthy cardiomyocytes, CSN6 interacts with the desmosomal complex (via DSP and PKP2) at the cardiac cell-cell junction. CSN6 inhibits activity of cullin E3 ligases by removing Nedd8 modifications to prevent desmosomal degradation/dissolution. The intact desmosomes tightly attach two adjacent cells together to maintain the mechanical integrity and proper electrical conduction. Calpain has limited accessibility to the cardiac desmosome. (b) Desmosomal mutations result in the destabilization of CSN6-desmosmal interaction. Absence of CSN6 allows attachment of Nedd8 and activates Cullin E3 ligases, which polyubiquitinate desmosomal proteins. Polyubiquitinated desmosomal proteins are cleared by proteasome or autolysosome, leading to desmosomal structural dissolution. Desmosomal mutations also increase the surface exposure to calpain and trigger their vulnerability to calpain-mediated degradation

• 

  Fig. 2. Arrhythmogenic pathways linked to desmosomal mutations and loss. (a) Healthy desmosomes enable proper connexin function for action potential propagation, calcium handling, and sodium channel activity. (b) Desmosomal loss triggers early connexin channel remodeling, which prevents proper electrical coupling between adjacent cardiomyocytes. (c) PKP2 loss causes calcium dysfunction through multiple mechanisms impacting connexin hemichannel permeability and PKC-driven increase in RYR2 activity (Ca2+ release from sarcoplasmic reticulum). (d) PKP2 missense mutations and loss can drive distinct mechanisms impacting sodium channel function, as well as localization

• 

  Fig. 3. Schemata of inflammatory response associated with ARVC. (1) Within healthy desmosomes, two adjacent cardiac cells are tightly connected. In the setting of desmosomal mutations, truncated/fragmented desmosomal proteins start to fall apart from cell membranes, which leads to the cell death and release of specific antigens (e.g., unmasked DSG2). (2) In the setting of desmosomal mutations/loss, inflammatory pathways, such as NF-κB signaling is activated, resulting in upregulation of target gene expression and chemokine/cytokine secretion, activation of cell apoptosis/necrosis, and cell proliferation. Small molecular Bay 11-7082 could inhibit the activation of NF-κB and reverse the disease progression. (3) The immune activation includes release of chemokines/cytokines, recruitment of immune cell types (e.g., neutrophils, T-cell, and macrophage) targeted to cardiomyocytes. Inflammatory infiltration further triggers cardiac cell death and fibrotic scar formation