Additive Promotion of Viral Internal Ribosome Entry Site-Mediated Translation by Far Upstream Element-Binding Protein 1 and an Enterovirus 71-Induced Cleavage Product

Abstract

The 5' untranslated region (5' UTR) of the enterovirus 71 (EV71) RNA genome contains an internal ribosome entry site (IRES) that is indispensable for viral protein translation. Due to the limited coding capacity of their RNA genomes, EV71 and other picornaviruses typically recruit host factors, known as IRES trans-acting factors (ITAFs), to mediate IRES-dependent translation. Here, we show that EV71 viral proteinase 2A is capable of cleaving far upstream element-binding protein 1 (FBP1), a positive ITAF that directly binds to the EV71 5' UTR linker region to promote viral IRES-driven translation. The cleavage occurs at the Gly-371 residue of FBP1 during the EV71 infection process, and this generates a functional cleavage product, FBP11-371. Interestingly, the cleavage product acts to promote viral IRES activity. Footprinting analysis and gel mobility shift assay results showed that FBP11-371 similarly binds to the EV71 5' UTR linker region, but at a different site from full-length FBP1; moreover, FBP1 and FBP11-371 were found to act additively to promote IRES-mediated translation and virus yield. Our findings expand the current understanding of virus-host interactions with regard to viral recruitment and modulation of ITAFs, and provide new insights into translational control during viral infection.

The master regulator FUBP1: its emerging role in normal cell function and malignant development

“…FUBP1 activates the effective viral replication of HCV and enterovirus 71 (EV71), two positive single-stranded RNA viruses belonging to the Flaviviridae and Picornaviridae families respectively [74,[86][87][88].…”

“…FUBP1 binds on the IRES within the 5' UTR of EV71 and enhances viral translation and viral growth in various cell lysates [74,87,88]. FUBP1 binds an AU-rich linker region (nucleotides 686 to 714), identified by EMSA (Table 1) [86,88]. Following EV71 infection, FUBP1 is recruited to the 5'UTR IRES, and enhanced viral translation.…”

HnRNP A1 Alters the Structure of a Conserved Enterovirus IRES Domain to Stimulate Viral Translation

“…Biochemical reconstitution experiments show that a single ITAF, PCPB2, along with several eIFs are necessary and sufficient to internally recruit the ribosome [8]; however, a growing body of cellular evidence indicate that efficient viral translation and replication require multiple host RNA binding proteins, executing their functions through interactions with the viral 5′-UTR [13, 18, 19, 47–49]. It is important to not overlook these discrepancies but instead attempt to better characterize 5′-UTR RNA elements and protein-IRES interactions that exhibit virological function.…”

Translation control of Enterovirus A71 gene expression

“…Thus, SRp20 may also function in facilitating EV-A71 translation. EV-A71 viral proteinase 2A pro can cleave FBP1 to generates a functional cleavage product, FBP1 , and the cleavage product also acts to promote viral IRES-mediated translation [60] (Fig. 3).…”