Functions of the 5′ and 3′ ends of calicivirus genomes

Alhatlani, Bader Y.; Vashist, Surender; Goodfellow, Ian

doi:10.1016/j.virusres.2015.02.002

Cited by 49 publications

(52 citation statements)

References 62 publications

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“…For instance, during vRNA replication of RNA viruses, vRI-dsRNAs must be efficiently unwound, thereby releasing nascently synthesized progeny vRNAs from vRNA templates. Moreover, viral genomic and antigenomic RNAs contain multiple cis-acting elements, highly structured RNA regions that usually play pivotal roles in the replication, translation, and encapsidation of vRNAs (11,51). Sometimes, a specific RNA structure required for one vRNA function, like translation or encapsidation, may need disruption and refolding to facilitate another vRNA function, like vRNA replication, and vice versa.…”

Section: Discussionmentioning

confidence: 99%

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Human Norovirus NS3 Has RNA Helicase and Chaperoning Activities

Hosmillo

Schwanke

et al. 2018

J Virol

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RNA-remodeling proteins, including RNA helicases and chaperones, act to remodel RNA structures and/or protein-RNA interactions and are required for all processes involving RNAs. Although many viruses encode RNA helicases and chaperones, their activities and their roles in infected cells largely remain elusive. Noroviruses are a diverse group of positive-strand RNA viruses in the family and constitute a significant and potentially fatal threat to human health. Here, we report that the protein NS3 encoded by human norovirus has both ATP-dependent RNA helicase activity that unwinds RNA helices and ATP-independent RNA-chaperoning activity that can remodel structured RNAs and facilitate strand annealing. Moreover, NS3 can facilitate viral RNA synthesis by norovirus polymerase. NS3 may therefore play an important role in norovirus RNA replication. Lastly, we demonstrate that the RNA-remodeling activity of NS3 is inhibited by guanidine hydrochloride, an FDA-approved compound, and, more importantly, that it reduces the replication of the norovirus replicon in cultured human cells. Altogether, these findings are the first to demonstrate the presence of RNA-remodeling activities encoded by and highlight the functional significance of NS3 in the noroviral life cycle. Noroviruses are a diverse group of positive-strand RNA viruses, which annually cause hundreds of millions of human infections and over 200,000 deaths worldwide. For RNA viruses, cellular or virus-encoded RNA helicases and/or chaperones have long been considered to play pivotal roles in viral life cycles. However, neither RNA helicase nor chaperoning activity has been demonstrated to be associated with any norovirus-encoded proteins, and it is also unknown whether norovirus replication requires the participation of any viral or cellular RNA helicases/chaperones. We found that a norovirus protein, NS3, not only has ATP-dependent helicase activity, but also acts as an ATP-independent RNA chaperone. Also, NS3 can facilitate viral RNA synthesis, suggesting the important role of NS3 in norovirus replication. Moreover, NS3 activities can be inhibited by an FDA-approved compound, which also suppresses norovirus replicon replication in human cells, raising the possibility that NS3 could be a target for antinoroviral drug development.

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Section: Discussionmentioning

confidence: 99%

“…For many RNA viruses, the viral RNA (vRNA) contains multiple cis-acting elements that play pivotal roles in vRNA replication, translation, and encapsidation during the viral life cycle (11)(12)(13). As with cellular RNA molecules, these elements are often highly structured in vRNAs and must be folded into the correct tertiary structures to be functional.…”

mentioning

confidence: 99%

Human Norovirus NS3 Has RNA Helicase and Chaperoning Activities

Hosmillo

Schwanke

et al. 2018

J Virol

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“…The family Caliciviridae is currently divided into five genera: Vesivirus, Lagovirus, Norovirus, Sapovirus, and Nebovirus. [1][2][3][4] Infections with noroviruses (NoVs) and sapoviruses (SaVs) are a global public health concern because they cause acute gastroenteritis outbreaks in people of all ages, and infections are difficult to prevent and control. 5,6 Efficient cell culture systems for human NoVs and SaVs have not been established.…”

Section: Introductionmentioning

confidence: 99%

Antiviral effect of theaflavins against caliciviruses

et al. 2016

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Caliciviruses are contagious pathogens of humans and various animals. They are the most common cause of viral gastroenteritis in humans, and can cause lethal diseases in domestic animals such as cats, rabbits and immunocompromised mice. In this study, we conducted cytopathic effect-based screening of 2080 selected compounds from our in-house library to find antiviral compounds against three culturable caliciviruses: feline calicivirus, murine norovirus (MNV) and porcine sapovirus (PoSaV). We identified active six compounds, of which two compounds, both related to theaflavins, showed broad antiviral activities against all three caliciviruses; three compounds (abamectin, a mixture of avermectin B1a and B1b; avermectin B1a; and (− )-epigallocatechin gallate hydrate) were effective against PoSaV only; and a heterocyclic carboxamide derivative (BFTC) specifically inhibited MNV infectivity in cell cultures. Further studies of the antiviral mechanism and structure-activity relationship of theaflavins suggested the following: (1) theaflavins worked before the viral entry step; (2) the effect of theaflavins was time-and concentration-dependent; and (3) the hydroxyl groups of the benzocycloheptenone ring were probably important for the anti-calicivirus activity of theaflavins. Theaflavins could be used for the calicivirus research, and as potential disinfectants and antiviral reagents to prevent and control calicivirus infections in animals and humans.

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“…Discrete and conserved regions of the NoV genome contain the CRE at the 3¢ extremity of MNV and the sgRNA promoter, with a very high probability of conforming to a stem-loop structure [9,45]. Mutational analyses of MNV revealed that the stem-loop structures located at the 5¢ end of the genome are important for viral replication and that even synonymous mutations destabilize the stem-loop structures starting at the 5¢ end of the genomic and sgRNA [46]. Although the precise mechanism of internal ribosome entry site (IRES)mediated translation is unknown in picornaviruses, it has been suggested that they function as RNA chaperones to promote the correct folding of the RNA structure, facilitating the recruitment of translation initiation factors [47].…”

Section: Discussionmentioning

confidence: 99%

Nucleotide triphosphatase and RNA chaperone activities of murine norovirus NS3

Han

Lee

Kotiguda

et al. 2018

Journal of General Virology

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Modulation of RNA structure is essential in the life cycle of RNA viruses. Immediate replication upon infection requires RNA unwinding to ensure that RNA templates are not in intra-or intermolecular duplex forms. The calicivirus NS3, one of the highly conserved nonstructural (NS) proteins, has conserved motifs common to helicase superfamily 3 among six genogroups. However, its biological functions are not fully understood. In this study we report the oligomeric state and the nucleotide triphosphatase (NTPase) and RNA chaperone activities of the recombinant full-length NS3 derived from murine norovirus (MNV). The MNV NS3 has an Mg 2+ -dependent NTPase activity, and site-directed mutagenesis of the conserved NTPase motifs blocked enzyme activity and viral replication in cells. Further, the NS3 was found via fluorescence resonance energy transfer (FRET)-based assays to destabilize double-stranded RNA in the presence of Mg 2+ or Mn 2+ in an NTPindependent manner. However, the RNA destabilization activity was not affected by mutagenesis of the conserved motifs of NTPase. These results reveal that the MNV NS3 has an NTPase-independent RNA chaperone-like activity, and that a FRETbased RNA destabilization assay has the potential to identify new antiviral drugs targeting NS3.

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Functions of the 5′ and 3′ ends of calicivirus genomes

Cited by 49 publications

References 62 publications

Human Norovirus NS3 Has RNA Helicase and Chaperoning Activities

Human Norovirus NS3 Has RNA Helicase and Chaperoning Activities

Antiviral effect of theaflavins against caliciviruses

Nucleotide triphosphatase and RNA chaperone activities of murine norovirus NS3

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