HIV-1 hypermethylated guanosine cap licenses specialized translation unaffected by mTOR.
HIV-1 hypermethylated guanosine cap licenses specialized translation unaffected by mTOR.
复制标题
DOI：
10.1073/pnas.2105153118
复制
发表时间：
2022-01-04
影响因子：
11.1
通讯作者：
Boris-Lawrie K
中科院分区：
文献类型：
--
作者：
Singh G;Seufzer B;Song Z;Zucko D;Heng X;Boris-Lawrie K
病毒病原体的增殖受到宿主的限制，但有弹性的病原体却能对抗宿主的限制。研究结果解释了HIV-1通过超甲基化阻断单甲基化鸟苷帽，并参与新的帽结合复合体进行病毒粒子蛋白翻译，而不受全局翻译抑制的影响。高甲基化的帽活性需要RNA结构依赖的RNA解旋酶A/DHX9的结合。eIF4E相互作用在编码病毒调节蛋白的完全剪接的HIV信使RNA模板上进行，因此催化位点mTOR抑制剂灭活eIF4E抑制了调节蛋白的翻译，而结构/辅助蛋白的翻译得以维持。两个相互排斥的翻译途径拮抗宿主并促进HIV-1在原代CD4+ T细胞中的增殖，从而损害宿主。eIF4E失活施加了一种抑制调节蛋白的操作变阻器，同时维持免疫细胞中病毒粒子的产生。附加在新生RNA聚合酶II转录本的5 '端是7-甲基鸟苷（m7G-cap），它与核帽结合复合体（CBC）结合，促进信使RNA （mRNA）成熟。成熟的mrna将CBC交换为eIF4E， eIF4E是通过mTOR控制的限速翻译因子。免疫细胞中的实验已经证明HIV-1未完全加工的转录本表现出m7G-cap的高甲基化，三甲基鸟苷合成酶-1的下调降低了HIV-1的感染性和病毒粒子蛋白的合成几个数量级。HIV-1帽超甲基化需要核RNA解旋酶A (RHA)/DHX9与5 '非翻译区（UTR）引物结合位点（PBS）片段的形状相互作用。在宿主翻译的全局下调过程中，RHA的下调或PBS片段的异常形状取消了高甲基化帽，降低了eIF4E与病毒粒子蛋白翻译的结合。抑制mTOR对HIV-1的增殖有害，并减弱Tat、Rev和Nef的合成。本研究确定了相互排斥的翻译途径，并通过病毒调节蛋白的从头合成来校准病毒粒子结构/辅助蛋白的合成。选择性病毒mRNA的高甲基化导致CBC交换到异二聚体CBP80/NCBP3，从而扩大了HIV-1在免疫细胞中的功能能力。
The proliferation of viral pathogens is restricted by hosts, but resilient pathogens antagonize the restriction by hosts. Findings explain that HIV-1 blocked mono-methylated guanosine cap by hypermethylation and engaged novel cap-binding complex for virion protein translation unaffected by global translation inhibition. The hypermethylated cap activity required RNA-structure-dependent binding of RNA helicase A/DHX9. eIF4E interaction proceeded on completely spliced HIV messenger RNA templates encoding viral regulatory proteins, thus eIF4E inactivation by catalytic site mTOR inhibitor suppressed regulatory protein translation, while structural/accessory protein translation was maintained. Two mutually exclusive translation pathways antagonize hosts and facilitate HIV-1 proliferation in primary CD4+ T cells to the detriment of hosts. eIF4E inactivation imposed an operational rheostat that suppressed regulatory proteins, while maintaining virion production in immune cells. Appended to the 5′ end of nascent RNA polymerase II transcripts is 7-methyl guanosine (m7G-cap) that engages nuclear cap-binding complex (CBC) to facilitate messenger RNA (mRNA) maturation. Mature mRNAs exchange CBC for eIF4E, the rate-limiting translation factor that is controlled through mTOR. Experiments in immune cells have now documented HIV-1 incompletely processed transcripts exhibited hypermethylated m7G-cap and that the down-regulation of the trimethylguanosine synthetase-1–reduced HIV-1 infectivity and virion protein synthesis by several orders of magnitude. HIV-1 cap hypermethylation required nuclear RNA helicase A (RHA)/DHX9 interaction with the shape of the 5′ untranslated region (UTR) primer binding site (PBS) segment. Down-regulation of RHA or the anomalous shape of the PBS segment abrogated hypermethylated caps and derepressed eIF4E binding for virion protein translation during global down-regulation of host translation. mTOR inhibition was detrimental to HIV-1 proliferation and attenuated Tat, Rev, and Nef synthesis. This study identified mutually exclusive translation pathways and the calibration of virion structural/accessory protein synthesis with de novo synthesis of the viral regulatory proteins. The hypermethylation of select, viral mRNA resulted in CBC exchange to heterodimeric CBP80/NCBP3 that expanded the functional capacity of HIV-1 in immune cells.
登录
查看更多内容
DOI：
10.2183/pjab.91.394
发表时间：
2015
期刊：
Proceedings of the Japan Academy. Series B, Physical and biological sciences
影响因子：
--
作者：
Furuichi Y
通讯作者：
Furuichi Y
影响因子：
3.7
作者：
Amorim R;Costa SM;Cavaleiro NP;da Silva EE;da Costa LJ
通讯作者：
da Costa LJ
影响因子：
4.8
作者：
Brady, Samantha;Singh, Gatikrushna;Heng, Xiao
通讯作者：
Heng, Xiao
影响因子：
6.7
作者：
Gebhardt, Anna;Bergant, Valter;Pichlmair, Andreas
通讯作者：
Pichlmair, Andreas
DOI：
10.1038/nri3198
发表时间：
2012-04-20
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--