PDF(Pubmed)
Abstract：
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 IRES trans-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, 3Cpro of 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.
OBJECTIVE: The 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.
OBJECTIVE: The 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.
摘要：
内部核糖体进入位点（IRES）元件构成顺式作用RNA调节序列，以不依赖帽的方式募集核糖体起始复合物，由各种RNA结合蛋白和IRES反式作用因子辅助。口蹄疫病毒（FMDV）含有功能性IRES元件，并利用该元件颠覆宿主翻译机制。我们的研究发现了一种新机制，其中RALY，属于RNA结合蛋白的异质核核糖核蛋白（hnRNP）家族的成员，通过其RNA识别基序残基与FMDVIRES的结构域3结合。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，我们的发现表明，RALY对FMDV复制的抑制作用不是归因于FMDVIRES介导的翻译起始复合物的组装，而是归因于与40S核糖体结合后80S核糖体复合物形成的障碍。相反，FMDV的3Cpro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,作为一种新型的关键IRES结合蛋白，通过阻断80S核糖体的形成来抑制FMDV的复制，提供对病毒如何招募和操纵宿主因素的更深入的了解。重要性由IRES元件驱动的FMDV基因组RNA的翻译是病毒感染的关键步骤。许多宿主蛋白被劫持以调节FMDVIRES依赖性翻译，但调控机制尚不清楚。这里,我们首次报道细胞RALY特异性地与FMDV的IRES相互作用,并通过阻断FMDVIRES上的80S核糖体组装来负调控病毒复制。相反，RALY介导的抑制通过泛素-蛋白酶体途径被病毒3C蛋白酶拮抗。这些结果将有助于进一步了解病毒感染过程中病毒与宿主的相互作用和翻译控制。
