A novel regulator of antiviral innate immune response in cardiomyocytes - Summary Innate immunity is increasingly recognized as a critical contributor to multiple cardiac pathological conditions. A better understanding of cardiomyocyte-autonomous innate immune response is crucial for developing more effective treatments for these conditions. Junctophilin-2 (JPH2), a protein essential for heart health, is traditionally believed to primarily responsible for facilitating Ca2+ induced Ca2+ release (CICR) within cardiomyocytes. However, our recent findings have revealed a novel function of JPH2 as a double-stranded RNA (dsRNA)-binding protein that sequesters dsRNA, thereby suppressing dsRNA-induced innate immune responses in cardiomyocytes. This newly identified function challenges traditional views of JPH2 in cardiac pathology, and suggests that self-RNA immunogenicity may play a previously unrecognized role in JPH2 deficiency induced heart failure. Additionally, our preliminary data indicate that dsRNA binding may induce structural changes in JPH2, potentially impacting JPH2’s role in CICR. This project seeks to address two key questions: (1) to what extent does self-RNA immunogenicity contribute to heart failure in the context of JPH2 deficiency, and (2) whether dsRNA binding induces JPH2 structural changes that alter its role in CICR. In Aim 1, we will determine the contribution of self-RNA immunogenicity and dsRNA-activated PKR to JPH2 KO-induced heart failure by using a CRISPR-mediated double-knockout mouse model and a synthetic dsRNA- sequestering protein. Aim 2 will address the structural changes in JPH2 upon dsRNA binding using Electron Paramagnetic Resonance, and assess the impact of cytosolic dsRNA on CICR machinery. This research is anticipated to redefine JPH2’s roles in cardiac biology, revealing new mechanisms of cardiac pathology and identifying potential therapeutic targets for cardiomyopathy. In addition, it will create novel mouse models and synthetic biology tools.
