Signaling initiated by type I interferon (IFN) results in the induction of hundreds of IFN-stimulated genes (ISGs). The type I IFN response is important for antiviral restriction, but aberrant activation of this response can lead to inflammation and autoimmunity. Regulation of this response is incompletely understood. We previously reported that the mRNA modification m⁶A and its deposition enzymes, METTL3 and METTL14 (METTL3/14), promote the type I IFN response by directly modifying the mRNA of a subset of ISGs to enhance their translation. Here, we determined the role of the RNA demethylase fat mass and obesity-associated protein (FTO) in the type I IFN response. FTO, which can remove either m⁶A or cap-adjacent m⁶Am RNA modifications, has previously been associated with obesity and body mass index, type 2 diabetes, cardiovascular disease, and inflammation. We found that FTO suppresses the transcription of a distinct set of ISGs, including many known pro-inflammatory genes, and that this regulation requires its catalytic activity but is not through the actions of FTO on m⁶Am. Interestingly, depletion of FTO led to activation of the transcription factor STAT3, whose role in the type I IFN response is not well understood. This activation of STAT3 increased the expression of a subset of ISGs. Importantly, this increased ISG induction resulting from FTO depletion was partially ablated by depletion of STAT3. Together, these results reveal that FTO negatively regulates STAT3-mediated signaling that induces proinflammatory ISGs during the IFN response, highlighting an important role for FTO in suppression of inflammatory genes.

由 I 型干扰素 (IFN) 启动的信号传导导致数百个 IFN 刺激基因 (ISG) 的诱导。I 型 IFN 反应对于抗病毒限制很重要，但这种反应的异常激活会导致炎症和自身免疫。对这种反应的调节还不完全清楚。我们之前报道过，mRNA 修饰 m ⁶ A 及其沉积酶 METTL3 和 METTL14 (METTL3/14) 通过直接修饰 ISG 子集的 mRNA 以增强其翻译来促进 I 型 IFN 反应。在这里，我们确定了 RNA 去甲基化酶脂肪量和肥胖相关蛋白 (FTO) 在 I 型干扰素反应中的作用。FTO，可以移除 m ⁶ A 或 cap-adjacent m ⁶Am RNA 修饰，以前与肥胖和体重指数、2 型糖尿病、心血管疾病和炎症有关。^{我们发现 FTO 抑制一组不同的 ISG 的转录，包括许多已知的促炎基因，并且这种调节需要其催化活性但不是通过 FTO 对 m 6}的作用是。有趣的是，FTO 的消耗导致转录因子 STAT3 的激活，其在 I 型 IFN 反应中的作用尚不清楚。STAT3 的这种激活增加了 ISG 子集的表达。重要的是，这种由 FTO 耗尽引起的 ISG 诱导增加被 STAT3 耗尽部分消融。总之，这些结果表明，FTO 负向调节 STAT3 介导的信号，在 IFN 反应期间诱导促炎 ISG，突出了 FTO 在抑制炎症基因中的重要作用。