Mouse Adenovirus Type 1 E4orf6 Induces PKR Degradation.
Mouse Adenovirus Type 1 E4orf6 Induces PKR Degradation.
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小鼠腺病毒 1 型 E4orf6 诱导 PKR 降解。
DOI：
10.1128/jvi.02063-21
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发表时间：
2022
影响因子：
5.4
通讯作者：
Spindler,KatherineR
中科院分区：
文献类型：
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作者：
Tejera-Hernández,Berto;Goodman,DanielleE;Nevarez,JuanM;Spindler,KatherineR
蛋白激酶 R (PKR) 是一种参与抗病毒反应的细胞激酶。该蛋白的失活或抑制是 DNA 和 RNA 病毒感染中的保守活性。与人类 5 型腺病毒不同，小鼠 1 型腺病毒 (MAV-1) 通过蛋白酶体依赖性降解抑制 PKR 活性。然而，这一过程发生的分子机制尚不完全清楚。我们研究了泛素化、MAV-1 早期区域 1B 55k (E1B 55k) 和早期区域 4 orf6 (E4orf6) 是否在 MAV-1 感染中的 PKR 降解中发挥作用，因为这些病毒蛋白的酶 3 (E3) 泛素连接酶活性在腺病毒科中是保守的。我们提供的证据表明 E4orf6 足以诱导小鼠 PKR 降解，并且蛋白酶体途径抑制可阻止 PKR 降解。抑制 cullin（E3 泛素连接酶复合物的一个组成部分）的 neddylation，可阻止 MAV-1 感染细胞中 PKR 的有效降解。最后，我们证明 MAV-1 对 PKR 的降解对小鼠 PKR 具有特异性。这些结果表明，两种腺病毒对抗 PKR 的机制在机制上是不同的。 重要性病毒已经进化到对抗免疫系统，以便在宿主中成功复制。几种抗病毒蛋白的下调对于有效的病毒感染很重要。蛋白激酶R（PKR）是一种抗病毒蛋白，属于宿主的第一道防线。由于 PKR 在病毒感染期间感知 dsRNA 并阻断细胞翻译过程，因此许多病毒抵消这种抗病毒活性也就不足为奇了。我们之前报道过小鼠 1 型腺病毒 (MAV-1) 感染期间 PKR 降解；然而，这种活性的分子机制尚不完全清楚。这项工作提供了有关 MAV-1 蛋白诱导 PKR 降解的证据，并扩展了有关蛋白酶体途径参与的知识。
Protein kinase R (PKR) is a cellular kinase involved in the antiviral response. The inactivation or inhibition of this protein is a conserved activity in DNA and RNA virus infections. In contrast to human adenovirus type 5, mouse adenovirus type 1 (MAV-1) inhibits PKR activity through proteasome-dependent degradation. However, the molecular mechanism by which this process takes place is not fully understood. We investigated whether ubiquitination, MAV-1 early region 1B 55k (E1B 55k), and early region 4 orf6 (E4orf6) play a role in PKR degradation in MAV-1 infection, because the enzyme 3 (E3) ubiquitin ligase activity with these viral proteins is conserved among theAdenoviridaefamily. We provide evidence that E4orf6 is sufficient to induce mouse PKR degradation and that proteasome pathway inhibition blocks PKR degradation. Inhibition of neddylation of cullin, a component of E3 ubiquitin ligase complex, blocked efficient PKR degradation in MAV-1-infected cells. Finally, we demonstrated that MAV-1 degradation of PKR is specific for mouse PKR. These results indicate that counteracting PKR is mechanistically different in two species of adenoviruses.IMPORTANCEViruses have evolved to counteract the immune system to successfully replicate in the host. Downregulation of several antiviral proteins is important for productive viral infection. Protein kinase R (PKR) is an antiviral protein that belongs to the first line of defense of the host. Because PKR senses dsRNA and blocks the cellular translation process during viral infections, it is not surprising that many viruses counteract this antiviral activity. We previously reported PKR degradation during mouse adenovirus type 1 (MAV-1) infection; however, the molecular mechanism of this activity was not fully known. This work provides evidence about the MAV-1 protein that induces PKR degradation and expands knowledge about involvement of the proteasome pathway.