Human cytomegalovirus IE2 drives transcription initiation from a select subset of late infection viral promoters by host RNA polymerase II.,PLoS Pathogens

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Human cytomegalovirus IE2 drives transcription initiation from a select subset of late infection viral promoters by host RNA polymerase II.
PLoS Pathogens ( IF 5.5 ) Pub Date : 2020-04-06 , DOI: 10.1371/journal.ppat.1008402
Ming Li _{1,

2} , Christopher B Ball ₂ , Geoffrey Collins ₂ , Qiaolin Hu ₁ , Donal S Luse ₃ , David H Price ₂ , Jeffery L Meier ₁

Affiliation

Herpesvirus late promoters activate gene expression after viral DNA synthesis has begun. Alphaherpesviruses utilize a viral immediate-early protein to do this, whereas beta- and gammaherpesviruses primarily use a 6-member set of viral late-acting transcription factors (LTF) that are drawn to a TATT sequence in the late promoter. The betaherpesvirus, human cytomegalovirus (HCMV), produces three immediate-early 2 protein isoforms, IE2-86, IE2-60, IE2-40, late in infection, but whether they activate late viral promoters is unknown. Here, we quickly degrade the IE2 proteins in late infection using dTag methodology and analyze effects on transcription using customized PRO-Seq and computational methods combined with multiple validation methods. We discover that the IE2 proteins selectively drive RNA Pol II transcription initiation at a subset of viral early-late and late promoters common to different HCMV strains, but do not substantially affect Pol II transcription of the 9,942 expressed host genes. Most of the IE2-activated viral late infection promoters lack the TATT sequence bound by the HCMV UL87-encoded LTF. The HCMV TATT-binding protein is not mechanistically involved in late RNA expression from the IE2-activated TATT-less UL83 (pp65) promoter, as it is for the TATT-containing UL82 (pp71) promoter. While antecedent viral DNA synthesis is necessary for transcription from the late infection viral promoters, continued viral DNA synthesis is unnecessary. We conclude that in late infection the IE2 proteins target a distinct subset of HCMV early-late and late promoters for transcription initiation by RNA Pol II. Commencement of viral DNA replication renders the HCMV genome late promoters susceptible to late-acting viral transcription factors.

中文翻译：

人类巨细胞病毒IE2通过宿主RNA聚合酶II从后期感染的病毒启动子的选定子集驱动转录起始。

疱疹病毒后期启动子在病毒DNA合成开始后激活基因表达。甲型疱疹病毒利用病毒的早期早期蛋白来做到这一点，而乙型和丙型疱疹病毒则主要使用一组六元的病毒后期作用转录因子（LTF），后者在晚期启动子中被绘制成TATT序列。β疱疹病毒是人巨细胞病毒（HCMV），在感染后期会产生三种即时早期的2种蛋白亚型，即IE2-86，IE2-60，IE2-40，但它们是否激活晚期病毒启动子尚不清楚。在这里，我们使用dTag方法快速降解晚期感染中的IE2蛋白，并使用定制的PRO-Seq和计算方法与多种验证方法相结合来分析对转录的影响。我们发现，IE2蛋白选择性地驱动不同的HCMV株共有的病毒早期-晚期和晚期启动子的子集的RNA Pol II转录起始，但基本上不影响9942个表达宿主基因的Pol II转录。大多数由IE2激活的病毒晚期感染启动子缺少HCMV UL87编码的LTF结合的TATT序列。HCMV TATT结合蛋白在机械上不参与IE2激活的无TATT的UL83（pp65）启动子的后期RNA表达，就像含TATT的UL82（pp71）启动子一样。虽然从后期感染的病毒启动子转录需要病毒DNA合成，但继续进行病毒DNA合成是不必要的。我们得出结论，在晚期感染中，IE2蛋白靶向HCMV早期和晚期启动子的不同子集，用于RNA Pol II的转录起始。病毒DNA复制的开始使HCMV基因组的晚期启动子易受后期作用的病毒转录因子的影响。

更新日期：2020-04-06

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