Essential Role for either TRS1 or IRS1 in Human Cytomegalovirus Replication
Essential Role for either TRS1 or IRS1 in Human Cytomegalovirus Replication
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DOI：
10.1128/jvi.02489-08
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发表时间：
2009-05-01
影响因子：
5.4
通讯作者：
Geballe, Adam P.
中科院分区：
文献类型：
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作者：
Marshall, Emily E.;Bierle, Craig J.;Geballe, Adam P.
病毒感染通常会产生双链 RNA (dsRNA)，进而引发有效的抗病毒反应，包括对蛋白激酶 R (PKR) 和 2'-5' 寡腺苷酸合成酶 (OAS) 介导的蛋白质合成的整体抑制。因此，许多病毒进化出了基因，例如编码 dsRNA 结合蛋白的基因，这些基因可以抵消这些途径。人类巨细胞病毒 (HCMV) 编码两种相关蛋白 pTRS1 和 pIRS1，它们与 dsRNA 结合并可以阻止 PKR 和 OAS 途径的激活。缺乏 IRS1 或 TRS1 的 HCMV 突变体在细胞培养物中至少复制得很好。然而，正如我们在本研究中所证明的，同时缺乏 IRS1 和 TRS1 (HCMV[Delta I/Delta T]) 的 HCMV 突变体具有严重的复制缺陷。 HCMV[Delta I/Delta T] 感染导致整体和病毒蛋白合成的深度抑制，以及真核起始因子 2 α (eIF2 α) 磷酸化的增加。痘苗病毒E3L基因可以替代IRS1或TRS1，从而实现HCMV复制。尽管dsRNA在HCMV感染的细胞中积累，但OAS途径仍然不活跃，即使在HCMVΔI/Delta T]感染的细胞中也是如此。这些结果表明，PKR 介导的 eIF2 α 磷酸化是主要的 dsRNA 激活途径，在 IRS1 和 TRS1 均不存在的情况下负责抑制蛋白质合成和 HCMV 复制，并且逃避 PKR 途径的要求可能解释了 IRS1 或 TRS1 对于生产性感染的必要性。
Viral infections often produce double-stranded RNA (dsRNA), which in turn triggers potent antiviral responses, including the global repression of protein synthesis mediated by protein kinase R (PKR) and 2'-5' oligoadenylate synthetase (OAS). As a consequence, many viruses have evolved genes, such as those encoding dsRNA-binding proteins, which counteract these pathways. Human cytomegalovirus (HCMV) encodes two related proteins, pTRS1 and pIRS1, which bind dsRNA and can prevent activation of the PKR and OAS pathways. HCMV mutants lacking either IRS1 or TRS1 replicate at least moderately well in cell culture. However, as we demonstrate in the present study, an HCMV mutant lacking both IRS1 and TRS1 (HCMV[Delta I/Delta T]) has a severe replication defect. Infection with HCMV[Delta I/Delta T] results in a profound inhibition of overall and viral protein synthesis, as well as increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2 alpha). The vaccinia virus E3L gene can substitute for IRS1 or TRS1, enabling HCMV replication. Despite the accumulation of dsRNA in HCMV-infected cells, the OAS pathway remains inactive, even in HCMV[Delta I/Delta T]-infected cells. These results suggest that PKR-mediated phosphorylation of eIF2 alpha is the dominant dsRNA-activated pathway responsible for inhibition of protein synthesis and HCMV replication in the absence of both IRS1 and TRS1 and that the requirement for evasion of the PKR pathway likely explains the necessity for IRS1 or TRS1 for productive infection.