HCV IRES Captures an Actively Translating 80S Ribosome

Yokoyama, Takeshi; Machida, Kodai; Iwasaki, W.; Shigeta, Tomoaki; Nishimoto, Madoka; Takahashi, Mari; Sakamoto, Ayako; Yonemochi, Mayumi; Harada, Yoshie; Shigematsu, Hideki; Shirouzu, Mikako; Tadakuma, Hisashi; Imataka, Hiroaki; Ito, Takuhiro

doi:10.1016/j.molcel.2019.04.022

Cited by 50 publications

(44 citation statements)

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“…In this way, the IRES "hitchhikes" with an actively translating ribosome until regular termination of the cap-dependent mRNA occurs. After termination, the HCV IRES is already present on the 40S subunit in cis and efficiently usurps the post-termination 40S subunit [166].…”

Section: Contacts Of the Hcv Ires With The Small Ribosomal 40s Subunimentioning

confidence: 99%

Hepatitis C Virus Translation Regulation

Niepmann

Gerresheim

2020

IJMS

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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.

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Section: Contacts Of the Hcv Ires With The Small Ribosomal 40s Subunimentioning

confidence: 99%

Hepatitis C Virus Translation Regulation

Niepmann

Gerresheim

2020

IJMS

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“…The functional HCV IRES consists of three parts: the long arm, the short arm and the body. In the liver, HCV hijacks the translating 80S ribosome by using miR-122 to alter the fold of the IRES body in order to bind to the 40S platform [22]. However, it is currently unknown how persistent infection in non-hepatic cells, which are deficient in miR-122, is established.…”

Section: Introductionmentioning

confidence: 99%

Various miRNAs compensate the role of miR-122 on HCV replication

Ono

Fukuhara

et al. 2020

PLoS Pathog

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One of the determinants for tissue tropism of hepatitis C virus (HCV) is miR-122, a liver-specific microRNA. Recently, it has been reported that interaction of miR-122 to HCV RNA induces a conformational change of the 5'UTR internal ribosome entry site (IRES) structure to form stem-loop II structure (SLII) and hijack of translating 80S ribosome through the binding of SLIII to 40S subunit, which leads to efficient translation. On the other hand, low levels of HCV-RNA replication have also been detected in some non-hepatic cells; however, the details of extrahepatic replication remain unknown. These observations suggest the possibility that miRNAs other than miR-122 can support efficient replication of HCV-RNA in nonhepatic cells. Here, we identified a number of such miRNAs and show that they could be divided into two groups: those that bind HCV-RNA at two locations (miR-122 binding sites I and II), in a manner similar to miR-122 (miR-122-like), and those that target a single site that bridges sites I and II and masking both G28 and C29 in the 5'UTR (non-miR-122-like). Although the enhancing activity of these non-hepatic miRNAs were lower than those of miR-122, substantial expression was detected in various normal tissues. Furthermore, structural modeling indicated that both miR-122-like and non-miR-122-like miRNAs not only can facilitate the formation of an HCV IRES SLII but also can stabilize IRES 3D structure in order to facilitate binding of SLIII to the ribosome. Together, these results suggest that HCV facilitates miR-122-independent replication in non-hepatic cells through recruitment of miRNAs other than miR-122. And our findings can provide a more detailed mechanism of miR-122dependent enhancement of HCV-RNA translation by focusing on IRES tertiary structure.

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“…The positive-sense RNA genome of Flaviviridae family members contains a single open reading frame (ORF) flanked by the 5′ and 3′ non translated region (NTR). The ORF is translated to a single polyprotein, either via cap-dependent translation (flavivirus) or internal ribosome entry site (IRES)-mediated translation (hepacivirus, pegivirus, and pestivirus) [ 5 , 6 , 7 ]. The viral polyprotein is processed by the host and viral proteases, co- and -post-translationally, into 9 to 12 mature proteins, consisting of the structural proteins, including Capsid or Core (C) and envelope (E) glycoproteins, and nonstructural (NS) proteins [ 1 , 4 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Delayed by Design: Role of Suboptimal Signal Peptidase Processing of Viral Structural Protein Precursors in Flaviviridae Virus Assembly

Alzahrani

Shanmugam

et al. 2020

Viruses

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The Flaviviridae virus family is classified into four different genera, including flavivirus, hepacivirus, pegivirus, and pestivirus, which cause significant morbidity and mortality in humans and other mammals, including ruminants and pigs. These are enveloped, single-stranded RNA viruses sharing a similar genome organization and replication scheme with certain unique features that differentiate them. All viruses in this family express a single polyprotein that encodes structural and nonstructural proteins at the N- and C-terminal regions, respectively. In general, the host signal peptidase cleaves the structural protein junction sites, while virus-encoded proteases process the nonstructural polyprotein region. It is known that signal peptidase processing is a rapid, co-translational event. Interestingly, certain signal peptidase processing site(s) in different Flaviviridae viral structural protein precursors display suboptimal cleavage kinetics. This review focuses on the recent progress regarding the Flaviviridae virus genus-specific mechanisms to downregulate signal peptidase-mediated processing at particular viral polyprotein junction sites and the role of delayed processing at these sites in infectious virus particle assembly.

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HCV IRES Captures an Actively Translating 80S Ribosome

Cited by 50 publications

References 50 publications

Hepatitis C Virus Translation Regulation

Hepatitis C Virus Translation Regulation

Various miRNAs compensate the role of miR-122 on HCV replication

Delayed by Design: Role of Suboptimal Signal Peptidase Processing of Viral Structural Protein Precursors in Flaviviridae Virus Assembly

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