Boris-Lawrie Kathleen, Liebau Jessica, Hayir Abdullgadir, Heng Xiao
Department of Veterinary and Biomedical Sciences, Institute for Molecular Virology, University of Minnesota, Saint Paul, MN 55108, USA.
Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
Viruses. 2025 Mar 5;17(3):372. doi: 10.3390/v17030372.
Translation regulation is essential to the survival of hosts. Most translation initiation falls under the control of the mTOR pathway, which regulates protein production from mono-methyl-guanosine (m7G) cap mRNAs. However, mTOR does not regulate all translation; hosts and viruses alike employ alternative pathways, protein factors, and internal ribosome entry sites to bypass mTOR. Trimethylguanosine (TMG)-caps arise from hypermethylation of pre-existing m7G-caps by the enzyme TGS1 and are modifications known for snoRNA, snRNA, and telomerase RNA. New findings originating from HIV-1 research reveal that TMG-caps are present on mRNA and license translation via an mTOR-independent pathway. Research has identified TMG-capping of selenoprotein mRNAs, junD, TGS1, DHX9, and retroviral transcripts. TMG-mediated translation may be a missing piece for understanding protein synthesis in cells with little mTOR activity, including HIV-infected resting T cells and nonproliferating cancer cells. Viruses display a nuanced interface with mTOR and have developed strategies that take advantage of the delicate interplay between these translation pathways. This review covers the current knowledge of the TMG-translation pathway. We discuss the intimate relationship between metabolism and translation and explore how this is exploited by HIV-1 in the context of CD4+ T cells. We postulate that co-opting both translation pathways provides a winning strategy for HIV-1 to dictate the sequential synthesis of its proteins and balance viral production with host cell survival.
翻译调控对于宿主的生存至关重要。大多数翻译起始受mTOR信号通路的控制，该通路调节单甲基鸟苷（m7G）帽mRNA的蛋白质生成。然而，mTOR并不调控所有的翻译过程；宿主和病毒都会利用替代途径、蛋白质因子和内部核糖体进入位点来绕过mTOR。三甲基鸟苷（TMG）帽由TGS1酶对预先存在的m7G帽进行超甲基化产生，是已知存在于小核仁RNA（snoRNA）、小核RNA（snRNA）和端粒酶RNA中的修饰。来自HIV-1研究的新发现表明，TMG帽存在于mRNA上，并通过一条不依赖mTOR的途径许可翻译。研究已经确定了硒蛋白mRNA、junD、TGS1、DHX9和逆转录病毒转录本的TMG加帽情况。TMG介导的翻译可能是理解mTOR活性较低的细胞（包括HIV感染的静息T细胞和不增殖的癌细胞）中蛋白质合成的缺失环节。病毒与mTOR呈现出微妙的相互作用界面，并已开发出利用这些翻译途径之间微妙相互作用的策略。本综述涵盖了TMG翻译途径的当前知识。我们讨论了代谢与翻译之间的密切关系，并探讨了HIV-1在CD4+T细胞背景下是如何利用这种关系的。我们推测，同时利用这两种翻译途径为HIV-1提供了一种成功策略，使其能够决定其蛋白质的顺序合成，并在病毒产生与宿主细胞存活之间取得平衡。
