TRIM25 inhibits influenza A virus infection, destabilizes viral mRNA, but is redundant for activating the RIG-I pathway.
TRIM25 inhibits influenza A virus infection, destabilizes viral mRNA, but is redundant for activating the RIG-I pathway.
复制标题
TRIM25抑制甲型流感病毒感染，破坏病毒mRNA的稳定性，但对于激活RIG-I通路是冗余的。
DOI：
10.1093/nar/gkac512
复制
发表时间：
2022-07-08
影响因子：
14.9
通讯作者：
Michlewski, Gracjan
中科院分区：
文献类型：
--
作者：
Choudhury, Nila Roy;Trus, Ivan;Heikel, Gregory;Wolczyk, Magdalena;Szymanski, Jacek;Bolembach, Agnieszka;Pinto, Rute Maria Dos Santos;Smith, Nikki;Trubitsyna, Maryia;Gaunt, Eleanor;Digard, Paul;Michlewski, Gracjan
E3泛素连接酶TRIM 25是对RNA病毒的先天免疫应答中的关键因子。TRIM 25已被证明在视黄酸诱导基因-1（RIG-I）途径中发挥作用，该途径在病毒感染后触发1型干扰素的表达。我们和其他人已经表明TRIM 25是一种RNA结合蛋白;然而，TRIM 25 RNA结合在对RNA病毒的先天免疫应答中的作用尚不清楚。在这里，我们证明了TRIM 25抑制甲型流感病毒（IAV A/PR/8/34_NS1（R38 A/K41 A））感染。令人惊讶的是，先前鉴定的RNA结合缺陷突变体TRIM 25 ΔRBD和E3泛素连接酶突变体TRIM 25 ΔRING，其缺乏E3泛素连接酶活性，仍然抑制IAV复制。此外，我们表明，在人源性培养细胞中，由IAV衍生的5′-三磷酸RNA或IAV本身介导的RIG-I/1型干扰素途径的激活不需要TRIM 25活性。此外，我们提出了新的证据，而不是TRIM 25直接抑制IAV转录，它结合和不稳定IAV mRNA。最后，我们表明TRIM 25与RNA的直接连接足以下调靶向RNA。总之，我们的研究结果揭示了TRIM 25用于抑制IAV感染和调节RNA代谢的潜在机制。
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 shown that TRIM25 is an RNA-binding protein; however, the role of TRIM25 RNA-binding in the innate immune response to RNA viruses is unclear. Here, we demonstrate that influenza A virus (IAV A/PR/8/34_NS1(R38A/K41A)) infection is inhibited by TRIM25. Surprisingly, previously identified RNA-binding deficient mutant TRIM25ΔRBD and E3 ubiquitin ligase mutant TRIM25ΔRING, which lack E3 ubiquitin ligase activity, still inhibited IAV replication. Furthermore, we show that in human-derived cultured cells, activation of the RIG-I/interferon type 1 pathway mediated by either an IAV-derived 5′-triphosphate RNA or by IAV itself does not require TRIM25 activity. Additionally, we present new evidence that instead of TRIM25 directly inhibiting IAV transcription it binds and destabilizes IAV mRNAs. Finally, we show that direct tethering of TRIM25 to RNA is sufficient to downregulate the targeted RNA. In summary, our results uncover a potential mechanism that TRIM25 uses to inhibit IAV infection and regulate RNA metabolism.
登录
查看更多内容
DOI：
10.1002/wrna.1679
发表时间：
2022-03
期刊：
Wiley interdisciplinary reviews. RNA
影响因子：
--
作者：
Gaunt ER;Digard P
通讯作者：
Digard P
影响因子：
16
作者：
Inn KS;Gack MU;Tokunaga F;Shi M;Wong LY;Iwai K;Jung JU
通讯作者：
Jung JU
影响因子：
7.6
作者：
Furuta, Yousuke;Gowen, Brian B.;Takahashi, Kazumi;Shiraki, Kimiyasu;Smee, Donald F.;Barnard, Dale L.
通讯作者：
Barnard, Dale L.
影响因子：
4
作者：
Hayman, Thomas J.;Hsu, Alan C.;Nicholson, Sandra E.
通讯作者：
Nicholson, Sandra E.
影响因子：
5.4
作者：
Castanier C;Zemirli N;Portier A;Garcin D;Bidère N;Vazquez A;Arnoult D
通讯作者：
Arnoult D