Loss of MEF2A induces replicative stress responses that trigger IFN production. 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

干扰素（Interferons, IFN）可通过病原体识别受体感知自身与非自身的RNA或DNA而被诱导产生。具体而言，胞质核酸异常蓄积或DNA损伤蓄积，均可激活STING（干扰素基因刺激因子）通路以诱导干扰素产生。尽管异常的自身DNA感知可引发自身免疫，但负调控因子可对上述过程起到抑制作用。本研究发现MEF2A是一种新型炎症负调控因子，可在稳态下抑制干扰素的诱导产生。研究表明，MEF2A缺陷可通过依赖STING但不依赖cGAS（环GMP-AMP合酶，cyclic GMP-AMP synthase）的方式，自发诱导I型干扰素产生，并显著激活下游干扰素刺激基因（Interferon Stimulated Genes, ISG）的表达。实验证实，MEF2A敲低所引发的干扰素应答，可帮助细胞抵御嗜心肌病毒感染。我们发现，MEF2A缺失会激活复制应激应答，进而通过DDX41/STING依赖的方式促进I型干扰素应答的产生。复制应激应答依赖于ATR（共济失调毛细血管扩张症和Rad3相关激酶，Ataxia telangiectasia and Rad3-related kinase）激酶的活性，因为抑制ATR可阻断STING的激活与I型干扰素的产生。综上，本研究将MEF2A与不同细胞类型中因复制应激应答引发的适应性不良I型干扰素应答的保护作用联系起来，同时也将DDX41依赖的STING激活与复制应激应答建立了关联。实验整体设计：取自AC16心肌细胞的Mock组与MEF2Ai组RNA样本；在野生型（Wild Type, WT）与DDX41缺陷细胞中，通过小干扰RNA（Small interfering RNA, siRNA）敲低MEF2A后的基因表达分析。