Hepatitis C Virus Translation Regulation

Abstract

Translation of the hepatitis C virus (HCV) RNA genome is regulated by the internal ribosome entry site (IRES), located in the 5’-untranslated region (5′UTR) and part of the core protein coding sequence, and by the 3′UTR. The 5′UTR has some highly conserved structural regions, while others can assume different conformations. The IRES can bind to the ribosomal 40S subunit with high affinity without any other factors. Nevertheless, IRES activity is modulated by additional cis sequences in the viral genome, including the 3′UTR and the cis-acting replication element (CRE). Canonical translation initiation factors (eIFs) are involved in HCV translation initiation, including eIF3, eIF2, eIF1A, eIF5, and eIF5B. Alternatively, under stress conditions and limited eIF2-Met-tRNAiMet availability, alternative initiation factors such as eIF2D, eIF2A, and eIF5B can substitute for eIF2 to allow HCV translation even when cellular mRNA translation is downregulated. In addition, several IRES trans-acting factors (ITAFs) modulate IRES activity by building large networks of RNA-protein and protein–protein interactions, also connecting 5′- and 3′-ends of the viral RNA. Moreover, some ITAFs can act as RNA chaperones that help to position the viral AUG start codon in the ribosomal 40S subunit entry channel. Finally, the liver-specific microRNA-122 (miR-122) stimulates HCV IRES-dependent translation, most likely by stabilizing a certain structure of the IRES that is required for initiation.

Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication

“…The HCV genome is a positive-sense RNA (i.e., of mRNA polarity) of about 9600 nucleotides (nts) in length [22]. After entry into the cytoplasm of the cell, the plus-strand genome can be directly translated by virtue of the internal ribosome entry site (IRES) ( Figure 1) [23,24]. The product of the viral polyprotein open reading frame (ORF) is a precursor protein that is co-and posttranslationally processed into the mature gene products [8,[25][26][27], including the structural proteins with the core protein acting as a nucleocapsid protein, and the envelope proteins that are incorporated in the viral lipid envelope.…”

“…The gene segment for the NS5B replicase is located at the end of the polyprotein ORF. The HCV RNA genome contains several cis-elements, which are involved in the regulation of translation and genome replication [23,[29][30][31]. In the 5′UTR, the internal ribosome entry site (IRES) element mediates translation of the polyprotein ORF.…”

“…The viral translation is regulated cap-independently by the IRES [23,24], and the RNA cis elements involved in the regulation of virus genome replication largely reside in the untranslated regions (UTRs) at the genome ends. In the 5 UTR, these cis elements include the 5 -terminal stem-loops (SL) I and II and the region in between that is used for binding of the liver-specific microRNA (miR) 122.…”

“…In addition, a variety of regulatory elements is found, in particular, in the NS5B coding region at the end of the coding region [23,30,31,[40][41][42][43][44]. The most prominent of these cis-regulatory RNA elements in the NS5B coding region is the cis replication element (CRE) (also called 5BSL3.2) that is required for replication [45].…”

“…However, this RNA region can also bind the small ribosomal 40S subunit [50], and it has been reported to be involved in translation regulation [51]. The 3 UTR is-in addition to its role in replication-involved in translation stimulation [23,52,53], and it can also bind the ribosomal 40S subunit [54]. Moreover, the CRE/5BSL3.2 and the 3 X interact with each other by virtue of a so-called "kissing loop" interaction that involves the apical loop of the CRE and the SL 2 of the 3 X region (when present in its three-stem-loop form) [31,39,55].…”