Histone Demethylase JMJD2D Suppresses Influenza A Virus Infection by Promoting RIG-I Expression

The efficacy of the host antiviral response against Influenza A virus (IAV), a leading cause of global pandemics, hinges upon the rapid recognition of the pathogen and the prompt activation of immune mechanisms. Nevertheless, the epigenetic landscape that orchestrates this antiviral response remains largely elusive. Here, we identify histone demethylase JMJD2D as a critical regulator in defense against IAV infection. A significant upregulation of JMJD2D expression was observed clinically in response to IAV infection, indicating that JMJD2D may play a role in regulating IAV infection. Indeed, JMJD2D-deficient mice exhibit increased susceptibility to IAV, characterized by elevated viral loads, severe lung tissue damage, and reduced survival rates, suggesting that JMJD2D plays an essential role in defense against IAV infection. Consistently, knockdown or pharmacological inhibition of JMJD2D in lung cells suppressed IAV replication and the IAV-triggered innate immune response. Mechanistically, JMJD2D suppressed IAV infection by removing H3K9me3 at the promoter region of retinoic acid inducible gene-I (RIG-I) and cooperating with NF-κB to enhance the expression of RIG-I, a critical sensor for IAV RNA. This study identifies JMJD2D as an epigenetic rheostat that governs RIG-I-mediated antiviral signaling, highlighting its potential as a therapeutic target for mitigating severe IAV infection.