Abstract 13301: TRIM29 Causes Pathogenesis of Viral Myocarditis by Inducing PERK-Mediated Endoplasmic Reticulum Stress and Reactive Oxygen Species Responses

Abstract

Introduction: Viral myocarditis is an inflammatory disease of the myocardium which contributes to a significant fraction of sudden death in children and young adults. The ongoing coronavirus disease 19 pandemic emphasizes the need for understanding the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Methods: To understand the role of the novel E3 ligase TRIM29 in controlling viral myocarditis, wild-type and TRIM29 knockout mice were infected with coxsackievirus B3 (CVB3) for inducing viral myocarditis. Mice survival and heart function were monitored by transthoracic echocardiography, and hearts were harvested for histology and immunohistochemistry analysis. Real-time PCR, western blotting, co-immunoprecipitation, enzyme-linked immunoassay, flow cytometry, over-expression and knockdown techniques were used to understand the pathogenic mechanisms of TRIM29 in regulating endoplasmic reticulum stress response after virus infection in this study. Results: We found that TRIM29 was highly induced by cardiotropic viruses, including CVB3 and encephalomyocarditis (EMCV), and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK) mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that restrict viral replication in cardiomyocytes in vitro . TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive cells in vivo . Mechanistically, TRIM29 interacted with PERK to catalyze SUMOylation of PERK for maintaining its stability, thereby promoting PERK-mediated signaling pathways. Conclusions: Our data provide the first evidence that TRIM29-mediated PERK signaling pathways cause pathogenesis of viral myocarditis and identify the TRIM29-PERK axis as a potential therapeutic target for treating viral induced cardiovascular diseases.