TRIM25 inhibits Influenza A infection by destabilising its mRNA and is redundant for the RIG-I pathway
TRIM25 inhibits Influenza A infection by destabilising its mRNA and is redundant for the RIG-I pathway
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DOI：
10.1101/2021.09.13.460052
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发表时间：
2021-09
期刊：
影响因子：
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通讯作者：
Nila Roy Choudhury;Gregory Heikel;Ivan Trus;R. M. Dos Santos Pinto;M. Trubitsyna;E. Gaunt;P. Digard;G. Michlewski
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文献类型：
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作者：
Nila Roy Choudhury;Gregory Heikel;Ivan Trus;R. M. Dos Santos Pinto;M. Trubitsyna;E. Gaunt;P. Digard;G. Michlewski
E3 泛素连接酶 TRIM25 是对 RNA 病毒的先天免疫反应的关键因素。 TRIM25 已被证明在视黄酸诱导基因 1 (RIG-I) 途径中发挥作用，该途径在病毒感染时触发 1 型干扰素的表达。我们和其他人最近证明 TRIM25 是一种 RNA 结合蛋白，但人们对 TRIM25 在 RNA 病毒先天免疫反应中的 RNA 结合作用知之甚少。在此，我们证明TRIM25可抑制甲型流感病毒（IAV A/PR/8/34_NS1(R38K41A)）感染。令人惊讶的是，缺乏E3泛素连接酶活性的宿主RNA结合缺陷突变体TRIM25ΔRBD和TRIM25ΔRING在TRIM25敲除细胞中挽救了IAV抑制作用。此外，我们发现在人类培养细胞中，由 IAV 衍生的 5'-三磷酸 RNA 介导的 RIG-I/1 型干扰素途径的激活不需要 TRIM25 活性。此外，敲除 TRIM25 不会影响 IAV 聚合酶的活性。我们提出了新的证据，表明 TRIM25 通过直接结合 IAV 的 mRNA 并使其不稳定来限制 IAV。最后，我们证明 TRIM25 与 RNA 的直接连接足以下调目标 RNA。总之，我们的结果揭示了 TRIM25 用于抑制 IAV 感染和调节 RNA 代谢的新机制。
The E3 ubiquitin ligase TRIM25 is a key factor in the innate immune response to RNA viruses. TRIM25 has been shown to play a role in the retinoic-acid-inducible gene-1 (RIG-I) pathway, which triggers expression of type 1 interferons upon viral infection. We and others have recently shown that TRIM25 is an RNA-binding protein, however not much is known about the RNA-binding roles of TRIM25 in the innate immune response to RNA viruses. Here, we demonstrate that influenza A virus (IAV A/PR/8/34_NS1(R38K41A)) infection is inhibited by TRIM25. Surprisingly, host RNA-binding deficient mutant TRIM25ΔRBD and TRIM25ΔRING, which lack E3 ubiquitin ligase activity rescued IAV inhibition in TRIM25 knock-out cells. Furthermore, we show that in human cultured cells activation of the RIG-I/interferon type 1 pathway mediated by an IAV-derived 5’-triphosphate RNA does not require TRIM25 activity. Additionally, knocking out TRIM25 does not affect the activity of the IAV polymerase. We present new evidence that TRIM25 restricts IAV by directly binding to and destabilising its mRNAs. Finally, we show that direct tethering of TRIM25 to RNA is sufficient to downregulate the targeted RNA. In summary, our results uncover a novel mechanism that TRIM25 uses to inhibit IAV infection and regulate RNA metabolism.