GSE209601
Loss of MEF2A induces replicative stress responses that trigger IFN production
Interferons (IFN) are induced by sensing of self and non-self RNA or DNA by pathogen recognition receptors. In particular, the aberrant accumulation of cytosolic nucleic acids or the accumulation of DNA lesions has the potential to activate the STING pathway to induce IFNs. While aberrant self-DNA sensing can cause autoimmunity, negative regulators keep these under check. Here we report that MEF2A is a novel negative regulator of inflammation which suppresses the induction of IFNs at homeostasis. We show that MEF2A deficiency results in the spontaneous induction of type I IFN and robust downstream ISG expression in a STING-dependent and cGAS-independent manner.  We demonstrate that the IFN response elicited by MEF2A depletion could protect cells from cardiotropic virus infections. We found that the loss of MEF2A triggered the replicative stress response to promote a DDX41/STING-dependent induction type I IFN response. The replicative stress response is dependent on ATR kinase activity, as inhibition of ATR abrogated STING activation and type I IFN production. Thus, our study connects MEF2A with protection from maladaptive type I IFN responses due to replicative stress response across various cell types as well as links the DDX41-dependent activation of STING to the replicative stress response. Overall design: Mock and MEF2Ai  RNA  samples from AC16 cardiomyocytes Gene expression following siRNA depletion of MEF2A in WT and DDX41 defficient cells