Host Shutoff Is a Conserved Phenotype of Gammaherpesvirus Infection and Is Orchestrated Exclusively from the Cytoplasm
Host Shutoff Is a Conserved Phenotype of Gammaherpesvirus Infection and Is Orchestrated Exclusively from the Cytoplasm
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DOI：
10.1128/jvi.01051-09
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发表时间：
2009-09-15
影响因子：
5.4
通讯作者：
Glaunsinger, Britt A.
中科院分区：
文献类型：
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作者：
Covarrubias, Sergio;Richner, Justin M.;Glaunsinger, Britt A.
卡波西肉瘤相关疱疹病毒 (KSHV) 和 Epstein-Barr 病毒 (EBV) 这两种人类伽玛疱疹病毒的裂解性感染会导致细胞转录组显着缺失。这种宿主关闭表型是由保守的疱疹病毒碱性核酸外切酶（在 KSHV 中称为 SOX，在 EBV 中称为 BGLF5）驱动的，在伽马疱疹病毒中，该酶已进化出遗传上可分离的靶向细胞 mRNA 的能力。我们现在表明，宿主关闭也是鼠伽马疱疹病毒 68 (MHV68) 感染的一个突出后果，该病毒被广泛用作研究这些病毒体内发病机制的模型系统。 MHV68 诱导的宿主关闭的效应器是其 SOX 同系物，此处称为 muSOX。 muSOX 宿主关闭活性与 KSHV SOX 的功能具有显着的功能保守性，包括最近描述的 SOX 诱导细胞核中 mRNA 过度腺苷酸化以及引起聚腺苷酸结合蛋白核重新定位的能力。 SOX 和 muSOX 定位于受感染细胞的细胞核和细胞质。使用这些蛋白质的空间受限变体，我们继续证明 SOX 和 muSOX 的所有已知的宿主关闭相关活性都是完全从细胞质中精心策划的。这些结果对于 SOX 和 muSOX 如何靶向细胞核中的新生细胞转录本具有重要的机制意义。此外，我们的研究结果将 MHV68 确立为一种新的、遗传上易于处理的模型，用于研究宿主关闭。
Lytic infection with the two human gammaherpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), leads to significant depletion of the cellular transcriptome. This host shutoff phenotype is driven by the conserved herpesviral alkaline exonuclease, termed SOX in KSHV and BGLF5 in EBV, which in gammaherpesviruses has evolved the genetically separable ability to target cellular mRNA. We now show that host shutoff is also a prominent consequence of murine gammaherpesvirus 68 (MHV68) infection, which is widely used as a model system to study pathogenesis of these viruses in vivo. The effector of MHV68-induced host shutoff is its SOX homolog, here termed muSOX. There is remarkable functional conservation of muSOX host shutoff activities with those of KSHV SOX, including the recently described ability of SOX to induce mRNA hyperadenylation in the nucleus as well as cause nuclear relocalization of the poly(A) binding protein. SOX and muSOX localize to both the nucleus and cytoplasm of infected cells. Using spatially restricted variants of these proteins, we go on to demonstrate that all known host shutoff-related activities of SOX and muSOX are orchestrated exclusively from the cytoplasm. These results have important mechanistic implications for how SOX and muSOX target nascent cellular transcripts in the nucleus. Furthermore, our findings establish MHV68 as a new, genetically tractable model to study host shutoff.