Keap1 recognizes EIAV early accessory protein Rev to promote antiviral defense.
Keap1 recognizes EIAV early accessory protein Rev to promote antiviral defense.
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DOI：
10.1371/journal.ppat.1009986
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发表时间：
2022-03
期刊：
影响因子：
6.7
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Wang Y;Ma G;Wang XF;Na L;Guo X;Zhang J;Liu C;Du C;Qi T;Lin Y;Wang X
Nrf 2/Keap 1轴在病毒易感性、病毒相关炎症和宿主细胞免疫调节中起着复杂的作用。然而，Nrf 2/Keap 1轴是否或如何参与马慢病毒与其宿主之间的相互作用仍不清楚。在这里，我们证明了Nrf 2/Keap 1轴在EIAV感染过程中被激活。EIAV-Rev与Keap 1竞争性结合，并从Keap 1介导的抑制中释放Nrf 2，导致Nrf 2在细胞核中积累，促进Nrf 2应答基因的转录。随后，我们证明了Nrf 2/Keap 1轴通过两种独立的分子机制抑制EIAV复制：直接增加抗氧化酶，以促进有效的细胞抵抗EIAV感染，并通过Keap 1和Rev之间的直接相互作用抑制Rev介导的RNA转运。总之，这些数据表明，Nrf 2/Keap 1轴的激活介导了对抗EIAV感染的被动防御反应。Nrf 2/Keap 1轴可能是开发对抗EIAV感染策略的潜在目标。在这里，我们报告，Nrf 2/Keap 1轴作为一个抗病毒效应对EIAV复制通过双向调节Rev。一方面，EIAV-Rev激活Nrf 2/Keap 1轴通过竞争性相互作用与Keap 1，并促进转录的细胞保护基因参与抗病毒反应。另一方面，Keap 1限制Rev/RRE依赖的RNA转运，导致抑制病毒蛋白合成和减少病毒复制。这项研究强调了Nrf 2/Keap 1轴在控制EIAV复制中的重要性，并将该途径确定为治疗慢病毒感染的潜在新切入点。重要的是，该报告提供了Nrf 2/Keap 1轴调节病毒复制的新见解。
The Nrf2/Keap1 axis plays a complex role in viral susceptibility, virus-associated inflammation and immune regulation in host cells. However, whether or how the Nrf2/Keap1 axis is involved in the interactions between equine lentiviruses and their hosts remains unclear. Here, we demonstrate that the Nrf2/Keap1 axis was activated during EIAV infection. Mechanistically, EIAV-Rev competitively binds to Keap1 and releases Nrf2 from Keap1-mediated repression, leading to the accumulation of Nrf2 in the nucleus and promoting Nrf2 responsive genes transcription. Subsequently, we demonstrated that the Nrf2/Keap1 axis represses EIAV replication via two independent molecular mechanisms: directly increasing antioxidant enzymes to promote effective cellular resistance against EIAV infection, and repression of Rev-mediated RNA transport through direct interaction between Keap1 and Rev. Together, these data suggest that activation of the Nrf2/Keap1 axis mediates a passive defensive response to combat EIAV infection. The Nrf2/Keap1 axis could be a potential target for developing strategies for combating EIAV infection. Here we report that the Nrf2/Keap1 axis acts as an antiviral effector on EIAV replication through two-way regulation of Rev. On the one hand, EIAV-Rev activates the Nrf2/Keap1 axis through a competitive interaction with Keap1, and promotes the transcription of cytoprotective genes implicated in the antiviral response. On the other hand, Keap1 restricts Rev/RRE-dependent RNA transport, leading to inhibition of viral protein synthesis and a reduction in viral replication. This study highlights the importance of the Nrf2/Keap1 axis in controlling EIAV replication, and identifies this pathway as a potential new entry-point for treating lentivirus infection. Importantly, this report provides new insights into the regulation of viral replication by the Nrf2/Keap1 axis.
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