Immunoglobulin Kappa Light Chain Produced by Cardiomyocytes and Participates in Maintaining Intercalated Disc...

In this study, we unexpectedly found that the immunoglobulin kappa light chain (Igκ) was expressed in normal cardiomyocytes of mice and humans, especially in intercalated discs (ICDs). Cardiomyocyte-specific knockout of Igκ in mice results in reduced myocardial contraction, atrioventricular block (AV block), and even sudden death. Histological analysis revealed that Igκ knockout in cardiomyocytes leads to structural disorder of ICDs, dissemination of the cytoskeleton proteins desmin and F-actin, as well as the loss of desmoplakin (DSP), N-cadherin, and connexin 43 (Cx43) on ICDs. Mechanistically, Igκ can bind to and stabilize plectin, a cytoskeleton-cross-linking protein that facilitates the assembly of desmin‒actin networks that maintain normal cytoskeletal architecture. Igκ can also anchor desmin to the DSP through plectin, thereby stabilizing the integrity of the ICDs. This molecular interplay critically reinforces cardiomyocyte cohesion and maintains structural and functional homeostasises. Our findings are the first to identify cardiomyocyte-expressed Igκ as a novel ICD-related molecule that participates in cardiomyocyte contraction and conduction by stabilizing plectins. Importantly, this work extends current arrhythmogenic cardiomyopathy (ACM) pathogenic models by revealing that ablation of the non-desmosomal gene Igκ disrupts ICD integrity, uncovering a new mechanism for non-desmosomal gene-related ACM and highlighting Igκ as a potential target for therapeutic investigations.