CCDC120 phase separation contributes to desmosomal integrity and cardiac function.

Desmosomes are cell-cell adhesive junctions that provide structural integrity and mechanical resistance to tissues. Disruptions in desmosome organization lead to severe cardiac and dermatological disorders. Emerging evidence reveals that desmosomes exhibit dynamic behaviors during remodeling. However, the mechanisms that initiate and regulate these dynamics under physiological conditions, and their correlation with desmosome-related disorders remain elusive. Here, we uncover the role of coiled-coil domain-containing 120 (CCDC120) in linking desmosomal organization to cardiac function via liquid-liquid phase separation (LLPS). CCDC120 localizes to desmosomes and is required for desmosomal integrity. CCDC120 exhibits LLPS properties and co-condenses with the desmosomal component plakophilin-2 (PKP2) during desmosomal assembly, forming dynamic condensates crucial for preserving desmosomal structure and junction stability. Moreover, CCDC120 condensates are modulated by PKCα phosphorylation. Loss of CCDC120 or altered CCDC120 phase separation properties leads to intercalated disc structure impairment and cardiac dysfunction in mice. Our findings propose a model wherein CCDC120 phase separation orchestrates desmosomal integrity, thereby establishing connections between desmosomal dynamics and the molecular etiology of cardiac dysfunction.