CCR4-NOT differentially controls host versus virus poly(a)-tail length and regulates HCMV infection.
CCR4-NOT differentially controls host versus virus poly(a)-tail length and regulates HCMV infection.
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DOI：
10.15252/embr.202256327
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发表时间：
2023-12-06
期刊：
影响因子：
7.7
通讯作者：
中科院分区：
文献类型：
--
作者：
与广泛刺激mRNA衰变并干扰宿主基因表达的大多数RNA和DNA病毒不同，人巨细胞病毒（HCMV）广泛重塑宿主翻译组而不产生mRNA衰变酶。通过在原代人成纤维细胞中进行靶向功能丧失筛选，我们在此将宿主CCR 4-NOT脱腺苷酶复合物成员hocT 1和hocT 3鉴定为选择性调节HCMV繁殖的非预期前病毒宿主因子。我们发现，支架亚基hocT 1是CCR 4-NOT-破坏细胞中晚期病毒基因表达和全基因组宿主反应所必需的。通过使用纳米孔直接RNA测序分析单个HCMV和宿主mRNA的poly（A）-尾长度，我们发现病毒信息的poly（A）-尾明显比细胞mRNA的poly（A）-尾更长，并且对CCR 4-NOT破坏的敏感性显着降低。我们的数据证实，宿主CCR 4-NOT的mRNA去腺苷化对HCMV的生产性复制至关重要，并定义了一种新的机制，即疱疹病毒感染破坏细胞mRNA代谢，重塑受感染细胞的基因表达景观。此外，我们暴露了一种意想不到的宿主因子，其有可能成为治疗性抗HCMV靶点。多亚基细胞去腺苷酸酶复合物CCR 4-NOT控制poly（A）-尾长度，调节mRNA衰变和翻译。HCMV需要CCR 4-NOT活性进行生产性感染，尽管其自身的mRNA对CCR 4-NOT降解不太敏感。
Unlike most RNA and DNA viruses that broadly stimulate mRNA decay and interfere with host gene expression, human cytomegalovirus (HCMV) extensively remodels the host translatome without producing an mRNA decay enzyme. By performing a targeted loss‐of‐function screen in primary human fibroblasts, we here identify the host CCR4‐NOT deadenylase complex members CNOT1 and CNOT3 as unexpected pro‐viral host factors that selectively regulate HCMV reproduction. We find that the scaffold subunit CNOT1 is specifically required for late viral gene expression and genome‐wide host responses in CCR4‐NOT‐disrupted cells. By profiling poly(A)‐tail lengths of individual HCMV and host mRNAs using nanopore direct RNA sequencing, we reveal poly(A)‐tails of viral messages to be markedly longer than those of cellular mRNAs and significantly less sensitive to CCR4‐NOT disruption. Our data establish that mRNA deadenylation by host CCR4‐NOT is critical for productive HCMV replication and define a new mechanism whereby herpesvirus infection subverts cellular mRNA metabolism to remodel the gene expression landscape of the infected cell. Moreover, we expose an unanticipated host factor with potential to become a therapeutic anti‐HCMV target. The multi‐subunit cellular deadenylase complex CCR4‐NOT controls poly(A)‐tail length, regulating mRNA decay and translation. HCMV requires CCR4‐NOT activity for productive infection, though its own mRNAs are less susceptible to CCR4‐NOT degradation.
协同稳定性使蛋白质复合物的形成更加稳健和可控。
影响因子：
4.6
作者：
Hsu, Kuan-Lun;Yen, Hsueh-Chi S.;Yeang, Chen-Hsiang
通讯作者：
Yeang, Chen-Hsiang
影响因子：
10.5
作者：
Burgess HM;Vink EI;Mohr I
通讯作者：
Mohr I
鼠巨细胞病毒M72在体内促进急性病毒复制，并且是Tric/CCT复合物的底物。
影响因子：
3.7
作者：
Gopal S;Perez E Jr;Xia AY;Knowlton JJ;Cerqueira F;Dermody TS;Upton JW
通讯作者：
Upton JW