Elusive Trans-Acting Factors Which Operate with Type I (Poliovirus-like) IRES Elements

Abstract

The phenomenon of internal initiation of translation was discovered in 1988 on poliovirus mRNA. The prototypic cis-acting element in the 5′ untranslated region (5′UTR) of poliovirus mRNA, which is able to direct initiation at an internal start codon without the involvement of a cap structure, has been called an IRES (Internal Ribosome Entry Site or Segment). Despite its early discovery, poliovirus and other related IRES elements of type I are poorly characterized, and it is not yet clear which host proteins (a.k.a. IRES trans-acting factors, ITAFs) are required for their full activity in vivo. Here we discuss recent and old results devoted to type I IRESes and provide evidence that Poly(rC) binding protein 2 (PCBP2), Glycyl-tRNA synthetase (GARS), and Cold Shock Domain Containing E1 (CSDE1, also known as UNR) are major regulators of type I IRES activity.

Role of RNA Domain Structure and Orientation in the Coxsackievirus B3 Virulence Phenotype

“…Stem-loop a and bulge loop b in domain IV bind PCBP2 ( 49 ), which also recruits the ITAF SRp20 ( 51 ). Domain V has interaction sites for eIF-4G, which also recruits eIF-4A ( 52 ) as well as the ITAF Unr ( 53 – 55 ) Importantly, the ITAF Unr binds with high affinity to both domain II and domain V in the context of the full-length 5′ UTR but binds with very low affinity to each individual domain ( 53 ), which suggests that these domains are positioned close together in 5′ UTRs that are most efficient. Based on the models we have generated, critical functional elements in the cloverleaf of domain I, the cruciform junction loop of domain IV, and the entirety of domain V are brought together in CVB3/28 with the critical apical hairpin loop of domain II nestled between.…”

Structure and function of type IV IRES in picornaviruses: a systematic review

“…The type I IRES in picornaviruses is composed of five principal domains, designated dII to dVI (Martinez-Salas et al, 2015). Translation initiation on PV IRES entails the scanning by 43S ribosomal preinitiation complexes, and engages a set of eIFs (eIF2,eIF3,eIF4A,eIF4G,eIF4B,and eIF1A) and a single ITAF, identified as the poly(C)-binding protein 2 (PCBP2), as shown in Figure 1A (Sweeney et al, 2014;Andreev et al, 2022). In instance of conventional pathways of translation initiation inaccessible, these viruses can employ an alternative IRES-independent transition mechanism, which depends on eIF2A/eIF2D and utilizes a non-AUG codon for initiation.…”