痘苗病毒(VACV),原型痘病毒,感染后积极重新编程宿主细胞代谢。然而,性质和分子机制在很大程度上仍然难以捉摸。鉴于细胞在不同生理环境中的不同营养暴露,了解VACV在不同营养条件下如何改变各种代谢途径是至关重要的.在这项研究中,我们确定了从头嘧啶生物合成在VACV感染中的重要性。我们阐明了痘苗生长因子(VGF)的意义,病毒早期蛋白和细胞表皮生长因子的同源物,使VACV能够在丝氨酸1859处磷酸化从头嘧啶途径的关键酶CAD,该位点已知正调节CAD活性。虽然营养不良的条件通常会抑制mTORC1的活化,VACV通过mTORC1-S6K1信号轴激活CAD,在缺乏谷氨酰胺和天冬酰胺的情况下。然而,与它的细胞同源物不同,表皮生长因子(EGF),在没有VACV感染的情况下,单独的VGF肽激活CAD的能力最小,提示在痘病毒进化过程中获得的其他病毒因子的参与和EGF的差异功能。我们的研究为理解重要的代谢途径的调节提供了基础。即,VACV感染期间嘧啶从头合成,为不同营养环境下的病毒调控提供新的思路。这项研究不仅有可能促进抗病毒治疗的发展,而且还改善了VACV作为溶瘤剂和疫苗载体的发展。
■我们的研究为VACV在不同营养线索下如何改变mTORC1-CAD信号轴提供了新的见解。鉴定VACV如何调节主要酶,CAD,在从头嘧啶合成途径中,建立了确定VACV如何重塑这一基本途径的分子机制,促进有效的VACV复制所必需的。我们进一步强调,尽管营养贫乏,通常抑制mTORC1激活,VACV可以刺激mTORC1。我们确定了它的早期生长因子,VGF,作为刺激mTORC1及其下游效应CAD的重要因素,揭示了在这些营养缺乏条件下VACV如何维持mTORC1-CAD轴活化的新机制。这项工作为mTORC1-CAD调控的分子机制提供了新的见解,它有可能被用来增强VACV作为溶瘤工具,疫苗载体和辅助抗病毒药物的开发。
Vaccinia virus (VACV), the prototype poxvirus, actively reprograms host cell metabolism upon infection. However, the nature and molecular mechanisms remain largely elusive. Given the diverse nutritional exposures of cells in different physiological contexts, it is essential to understand how VACV may alter various metabolic pathways in different nutritional conditions. In this study, we established the importance of de novo
pyrimidine biosynthesis in VACV infection. We elucidated the significance of vaccinia growth factor (VGF), a viral early protein and a homolog of cellular epidermal growth factor, in enabling VACV to phosphorylate the key enzyme CAD of the de novo
pyrimidine pathway at serine 1859, a site known to positively regulate CAD activity. While nutrient-poor conditions typically inhibit mTORC1 activation, VACV activates CAD via mTORC1-S6K1 signaling axis, in conditions where glutamine and asparagine are absent. However, unlike its cellular homolog, epidermal growth factor (EGF), VGF peptide alone in the absence of VACV infection has minimal ability to activate CAD, suggestive of the involvement of other viral factor(s) and differential functions to EGF acquired during poxvirus evolution. Our research provides a foundation for understanding the regulation of a significant metabolic pathway, namely, de novo
pyrimidine synthesis during VACV infection, shedding new light on viral regulation under distinct nutritional environments. This study not only has the potential to contribute to the advancement of antiviral treatments but also improve the development of VACV as an oncolytic agent and vaccine vector.