HuR Promotes IRES-Driven Translation of Senecavirus A by Facilitating the Formation of Translation Initiation Complexes

Senecavirus A (SVA), a member of the Picornaviridae family, has significance not only as an emerging pathogen in the swine industry but also as a potent oncolytic virus that causes neuroendocrine malignancies. For efficient reproduction, SVA deploys sophisticated tactics to hijack the host translational apparatus and initiate viral protein production via its internal ribosome entry site (IRES) element, although the underlying regulatory processes remain incompletely elucidated. In this study, we identified human antigen R (HuR), an established RNA-binding post-transcriptional regulator, as an upregulator of SVA IRES-driven translation and replication. We show that, upon SVA infection, HuR translocates from the nucleus to the cytoplasm, wherein it specifically promotes viral IRES-mediated translation by facilitating the formation of translation initiation complexes on the viral IRES. We also identified HuR’s C-terminal RNA recognition motif as perhaps the most important domain associated with this process. Further mechanistic analyses revealed that the viral proteins VP1, 2AB, and 3C pro synergistically promote the nucleocytoplasmic translocation of HuR via different mechanisms. Specifically, whereas VP1 physically interacts with HuR, thereby promoting its cytoplasmic localization, 2AB and 3C pro degrade the nucleoporin 62 and nucleoporin 214 via an autophagy-dependent pathway, thereby resulting in a disruption of nuclear pore complex permeability. Intriguingly, we also show that HuR may represent a conserved factor governing translation and infection in other IRES-containing picornaviruses and flaviviruses. Collectively, our findings in this study reveal a novel regulatory function of HuR in the initiation of IRES-driven translation, thereby highlighting its potential utility as a therapeutic target for broad-spectrum antiviral strategies. • HuR, an RNA-binding post-transcriptional regulator, was identified as a positive regulator of SVA IRES-driven translation. • SVA VP1, 2AB, and 3C pro act synergistically to alter the nucleocytoplasmic shuttling of HuR for efficient reproduction. • HuR promotes IRES-driven translation by supporting the assembly of translation initiation complexes on the viral IRES.