Verhamme Ruth, Jansens Robert J J, Liu Jianheng, Van Raemdonck Fien, Van Waesberghe Cliff, Nicholson Luke, Jaffrey Samie R, Favoreel Herman W
Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Department of Pharmacology, Weill Medical College, Cornell University, New York, New York, USA.
J Virol. 2025 Feb 25;99(2):e0201924. doi: 10.1128/jvi.02019-24. Epub 2025 Jan 10.
Alpha-ketoglutarate-dependent dioxygenase, also known as fat mass and obesity-associated protein (FTO), is an RNA demethylase that mediates the demethylation of N,2-O-dimethyladenosine (m6Am) and N-methyladenosine (m6A). Both m6Am and m6A are prevalent modifications in mRNA and affect different aspects of transcript biology, including splicing, nuclear export, translation efficiency, and degradation. The role of FTO during (herpes) virus infection remains largely unexplored. In this study, we show that the UL13 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) triggers phosphorylation of FTO. In primary epithelial cells, depletion of FTO leads to increased expression of antiviral interferon-stimulated genes (ISGs) and UL13 triggers FTO-dependent suppression of ISG expression. Although PRV infection suppresses m6Am levels in host small nuclear RNA, this is independent of UL13. The current data highlight FTO as an important regulator of antiviral ISG expression and suggest that UL13-mediated phosphorylation of FTO may serve as a previously unrecognized viral strategy to suppress the antiviral interferon response.IMPORTANCERNA modification pathways play important roles in diverse cellular processes and virus life cycles. Although previous studies have demonstrated that alphaherpesviruses can substantially influence cellular RNA modifications, such as m6A, the impact on the m6Am epitranscriptome machinery remains largely unexplored. The present work reports that the UL13 protein kinase of pseudorabies virus (PRV), an alphaherpesvirus, mediates phosphorylation of the m6Am/m6A eraser FTO and that this correlates with a UL13- and FTO-dependent suppression of antiviral interferon-stimulated gene (ISG) expression. Furthermore, PRV infection leads to a pronounced reduction in m6Am levels in host snRNA and also induces phosphorylation of the m6Am writer PCIF1. These data highlight FTO as an important regulator of ISG expression and reveal that viral manipulation of FTO, such as UL13-induced phosphorylation of FTO, may serve as a previously unrecognized interferon evasion strategy.
α-酮戊二酸依赖性双加氧酶，也称为脂肪量与肥胖相关蛋白（FTO），是一种RNA去甲基化酶，可介导N，2-O-二甲基腺苷（m6Am）和N-甲基腺苷（m6A）的去甲基化。m6Am和m6A都是mRNA中普遍存在的修饰，并且影响转录生物学的不同方面，包括剪接、核输出、翻译效率和降解。FTO在（疱疹）病毒感染期间的作用在很大程度上仍未得到探索。在本研究中，我们表明α疱疹病毒伪狂犬病病毒（PRV）的UL13蛋白激酶触发FTO的磷酸化。在原代上皮细胞中，FTO的耗竭导致抗病毒干扰素刺激基因（ISG）的表达增加，并且UL13触发FTO依赖性的ISG表达抑制。尽管PRV感染会抑制宿主小核RNA中的m6Am水平，但这与UL13无关。目前的数据突出了FTO作为抗病毒ISG表达的重要调节因子，并表明UL13介导的FTO磷酸化可能是一种以前未被认识的病毒策略，以抑制抗病毒干扰素反应。
重要性
RNA修饰途径在多种细胞过程和病毒生命周期中发挥重要作用。尽管先前的研究表明α疱疹病毒可以显著影响细胞RNA修饰，如m6A，但对m6Am表观转录组机制的影响在很大程度上仍未得到探索。目前的工作报道，α疱疹病毒伪狂犬病病毒（PRV）的UL13蛋白激酶介导m6Am/m6A擦除酶FTO的磷酸化，并且这与UL13和FTO依赖性的抗病毒干扰素刺激基因（ISG）表达抑制相关。此外，PRV感染导致宿主snRNA中m6Am水平显著降低，并且还诱导m6Am写入器PCIF1的磷酸化。这些数据突出了FTO作为ISG表达的重要调节因子，并揭示病毒对FTO的操纵，如UL13诱导的FTO磷酸化，可能是一种以前未被认识的干扰素逃避策略。
