Nuclear ribonucleoprotein RALY downregulates foot-and-mouth disease virus replication but antagonized by viral 3C protease
Nuclear ribonucleoprotein RALY downregulates foot-and-mouth disease virus replication but antagonized by viral 3C protease
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DOI：
10.1128/spectrum.03658-23
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发表时间：
2024-02-07
影响因子：
3.7
通讯作者：
Guo，Huichen
中科院分区：
文献类型：
--
作者：
Wu，Jin'en;Sun，Chao;Guo，Huichen
内部核糖体进入位点（IRES）元件构成一个顺式作用的RNA调控序列，在各种RNA结合蛋白和ireans作用因子的辅助下，以不依赖于帽的方式招募核糖体起始复合物。口蹄疫病毒（FMDV）含有一个功能性IRES元件，并利用该元件破坏宿主的翻译机制。我们的研究发现了一种新的机制，其中，异质核核糖核蛋白（hnRNP）家族的成员，属于RNA结合蛋白，通过其RNA识别基序残基结合到FMDV IRES的结构域3。这种相互作用通过抑制ires驱动的翻译导致FMDV复制的下调。此外，我们的研究结果表明，RALY对FMDV复制的抑制作用不是由于FMDV ires介导的翻译起始复合物的组装，而是由于80S核糖体与40S核糖体结合后阻碍了80S核糖体复合物的形成。相反，3Cproof FMDV通过泛素-蛋白酶体途径抵消raly介导的抑制。因此，这些结果表明，RALY作为一种新的关键ires结合蛋白，通过阻断80S核糖体的形成来抑制FMDV的复制，为病毒如何招募和操纵宿主因子提供了更深入的了解。IRES元件驱动的FMDV基因组RNA翻译是病毒感染的关键步骤。许多宿主蛋白被劫持来调节FMDV ires依赖的翻译，但其调节机制尚不清楚。在这里，我们首次报道了细胞RALY特异性地与FMDV的IRES相互作用，并通过阻断FMDV IRES上80S核糖体的组装来负向调节病毒复制。相反，raly介导的抑制被病毒3C蛋白酶通过泛素-蛋白酶体途径拮抗。这些结果将有助于进一步了解病毒与宿主的相互作用和病毒感染过程中的转译控制。
The internal ribosome entry site (IRES) element constitutes a cis-acting RNA regulatory sequence that recruits the ribosomal initiation complex in a cap-independent manner, assisted by various RNA-binding proteins and IREStrans-acting factors. Foot-and-mouth disease virus (FMDV) contains a functional IRES element and takes advantage of this element to subvert host translation machinery. Our study identified a novel mechanism wherein RALY, a member of the heterogeneous nuclear ribonucleoproteins (hnRNP) family belonging to RNA-binding proteins, binds to the domain 3 of FMDV IRES via its RNA recognition motif residue. This interaction results in the downregulation of FMDV replication by inhibiting IRES-driven translation. Furthermore, our findings reveal that the inhibitory effect exerted by RALY on FMDV replication is not attributed to the FMDV IRES-mediated assembly of translation initiation complexes but rather to the impediment of 80S ribosome complex formation after binding with 40S ribosomes. Conversely, 3Cproof FMDV counteracts RALY-mediated inhibition by the ubiquitin-proteasome pathway. Therefore, these results indicate that RALY, as a novel critical IRES-binding protein, inhibits FMDV replication by blocking the formation of 80S ribosome, providing a deeper understanding of how viruses recruit and manipulate host factors.IMPORTANCEThe translation of FMDV genomic RNA driven by IRES element is a crucial step for virus infections. Many host proteins are hijacked to regulate FMDV IRES-dependent translation, but the regulatory mechanism remains unknown. Here, we report for the first time that cellular RALY specifically interacts with the IRES of FMDV and negatively regulates viral replication by blocking 80S ribosome assembly on FMDV IRES. Conversely, RALY-mediated inhibition is antagonized by the viral 3C protease by the ubiquitin-proteasome pathway. These results would facilitate further understanding of virus-host interactions and translational control during viral infection.