Understanding the potential of hepatitis C virus internal ribosome entry site domains to modulate translation initiation via their structure and function

Abstract

Translation initiation in the hepatitis C virus (HCV) occurs through a cap-independent mechanism that involves an internal ribosome entry site (IRES) capable of interacting with and utilizing the eukaryotic translational machinery. In this review, we focus on the structural configuration of the different HCV IRES domains and the impact of IRES primary sequence variations on secondary structure conservation and function. In some cases, multiple mutations, even those scattered across different domains, led to restoration of the translational activity of the HCV IRES, although the individual occurrences of these mutations were found to be deleterious. We propose that such observation may be attributed to probable long-range inter- and/or intra-domain functional interactions. The precise functioning of the HCV IRES requires the specific interaction of its domains with ribosomal subunits and a subset of eukaryotic translation initiation factors (eIFs). The structural conformation, sequence preservation and variability, and translational machinery association with the HCV IRES regions are also thoroughly discussed, along with other factors that can affect and influence the formation of translation initiation complexes. WIREs RNA 2015, 6:211–224. doi: 10.1002/wrna.1268

Translation initiation by the hepatitis C virus IRES requires eIF1A and ribosomal complex remodeling

“…The IRES also binds directly to eIF3 (Sizova et al, 1998), which along with the eIF2-containing TC have been described as capable of progressing the HCV IRES preinitiation complex (PIC) to an elongation-competent 80S ribosome (Pestova et al, 1998b). These and other studies have pointed to a mechanism in which a naked (unbound by factors) 40S subunit first binds directly to the IRES RNA through interactions with dIII (Ji et al, 2004; Otto and Puglisi, 2004), placing the start codon into the P site of the decoding groove, followed by recruitment of eIF3 by IRES subdomain IIIb (dIIIb) and association of the TC to position Met-tRNA i Met to form a 48S* complex (asterisk denotes noncanonical assembly and composition) (reviewed in: [Fraser and Doudna, 2007; Khawaja et al, 2015]). Although biochemical data suggest a step-wise recruitment of essential translation components, it has also been suggested that the first step in HCV IRES-driven translation could be binding to an assembled 43S PIC (40S pre-bound by other factors) (Berry et al, 2010; Hellen, 2009; Jackson et al, 2010).…”

“…In both models, it is proposed that subsequent GTP hydrolysis by eIF2, directed by eIF5 and enhanced by IRES dII, induces factor release and subunit joining (Locker et al, 2007). Mutations to different parts of the HCV IRES inhibit specific steps in the pathway (Berry et al, 2010; Filbin and Kieft, 2011; Kieft et al, 2001; Sizova et al, 1998; Spahn et al, 2001) (reviewed in: [Khawaja et al, 2015; Lukavsky, 2009]), which is proposed to be similar in other type 3 IRESs (Kolupaeva et al, 2000; Pestova et al, 1998b; de Breyne et al, 2008). In addition, the HCV IRES can also initiate translation when eIF2 is inhibited by phosphorylation of its alpha subunit (Koev et al, 2002; Robert et al, 2006).…”

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

“…Similar to cardioviruses, HCV RNA expression is driven by IRES-mediated translation initiation [77]. Under cellular stress conditions, specific domains of HCV IRES interact with the small ribosomal subunit and the initiation factors eIF3 and eIF5B (Figure 1, left), allowing expression of viral RNA [79]. In addition, some viruses from other families unrelated to cardioviruses are known to target cells of the cardiovascular system and contribute to the etiology and progression of CVDs (for a detailed review, see [80]).…”

Viral internal ribosomal entry sites: four classes for one goal

“…The HCV 5′UTR contains four domains (I–IV) (Figure ). Whereas domains I and II are involved in viral replication, the IRES spans domains II and III and domain IV is present in HCV but absent in HCV‐like viruses . Interestingly, domain I contains two binding sites for a liver‐specific microRNA miR‐122 which activates HCV replication .…”