Human cytomegalovirus lytic infection inhibits replication-dependent histone synthesis and requires stem loop binding protein function.
Human cytomegalovirus lytic infection inhibits replication-dependent histone synthesis and requires stem loop binding protein function.
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DOI：
10.1073/pnas.2122174119
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发表时间：
2022-04-05
影响因子：
11.1
通讯作者：
Kalejta, Robert F.
中科院分区：
文献类型：
--
作者：
Albright, Emily R.;Morrison, Kylee;Ranganathan, Padhma;Carter, Dominique M.;Nishikiori, Masaki;Lee, Jeong-Hee;Slayton, Mark D.;Ahlquist, Paul;Terhune, Scott S.;Kalejta, Robert F.
到目前为止，还不知道致病的人类病毒是否、如何或为什么可能调节复制依赖(RD)组蛋白的从头产生，这些复制依赖(RD)组蛋白修饰感染细胞内它们的DNA基因组。我们的发现，人类巨细胞病毒(HCMV)抑制RD组蛋白的产生，证实了病毒针对这一基本的细胞过程。此外，我们发现HCMV诱导、重新定位并随后征用茎环结合蛋白(SLBP)而不是RD组蛋白合成来支持生产性复制，这一高度保守的蛋白具有其他功能的潜力。SLBP对于HCMV感染的关键性质和RD组蛋白合成对于细胞DNA复制的关键性质突出了这一过程作为未来抗病毒和化疗干预的目标。复制依赖(RD)组蛋白在感染开始时沉积在人类巨细胞病毒(HCMV)基因组上。我们研究了巨细胞病毒如何影响RD组蛋白的从头产生，并发现病毒感染阻止了RD组蛋白mRNAs的积累，这通常发生在S时期。此外，存在于HCMV感染细胞中的RD组蛋白mRNAs没有经过正常核输出和翻译所需的独特的3‘端加工。在细胞核中协调加工的蛋白质-干环结合蛋白(SLBP)主要在细胞质中被发现，在感染HCMV的细胞中RD组蛋白不是从头合成的。然而，有趣的是，我们发现SLBP是有效合成和组装感染性子代病毒粒子所必需的。我们的结论是，HCMV感染减弱了RD组蛋白mRNA的积累和加工以及RD组蛋白的从头合成，同时利用SLBP作为另一种目的来支持感染性病毒粒子的产生。
Until now, it was not known if, how, or why pathogenic human viruses might modulate the de novo production of the replication-dependent (RD) histone proteins that decorate their DNA genomes within infected cells. Our finding that human cytomegalovirus (HCMV) inhibits RD histone production affirms that a virus targets this fundamental cellular process. Furthermore, our revelation that HCMV induces, relocalizes, and then commandeers the stem loop–binding protein (SLBP) for a purpose other than RD histone synthesis to support productive replication illuminates the potential for other functions of this highly conserved protein. The critical nature of SLBP for HCMV infection and of RD histone synthesis for cellular DNA replication highlights this process as a target for future antiviral and chemotherapeutic interventions. Replication-dependent (RD) histones are deposited onto human cytomegalovirus (HCMV) genomes at the start of infection. We examined how HCMV affects the de novo production of RD histones and found that viral infection blocked the accumulation of RD histone mRNAs that normally occurs during the S phase. Furthermore, RD histone mRNAs present in HCMV-infected cells did not undergo the unique 3′ processing required for their normal nuclear export and translation. The protein that orchestrates processing in the nucleus, stem loop–binding protein (SLBP), was found predominantly in the cytoplasm, and RD histone proteins were not de novo synthesized in HCMV-infected cells. Intriguingly, however, we found that SLBP was required for the efficient synthesis and assembly of infectious progeny virions. We conclude that HCMV infection attenuates RD histone mRNA accumulation and processing and the de novo protein synthesis of the RD histones, while utilizing SLBP for an alternative purpose to support infectious virion production.
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影响因子：
3.7
作者：
Kristie, Thomas M.
通讯作者：
Kristie, Thomas M.
影响因子：
16
作者：
Dankert, John F.;Rona, Gergely;Clijsters, Linda;Geter, Phillip;Skaar, Jeffrey R.;Bermudez-Hernandez, Keria;Sassani, Elizabeth;Fenyo, David;Ueberheide, Beatrix;Schneider, Robert;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
16
作者：
Gruber, Joshua J.;Olejniczak, Scott H.;Yong, Jeongsik;La Rocca, Gaspare;Dreyfuss, Gideon;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
3.4
作者：
Carter DM;Westdorp K;Noon KR;Terhune SS
通讯作者：
Terhune SS
影响因子：
5.3
作者：
Koseoglu, M. Murat;Graves, Lee M.;Marzluff, William F.
通讯作者：
Marzluff, William F.