RNA chaperones encoded by RNA viruses

Yang, Jie; Xia, Hongjie; Qi, Qian; Zhou, Xi

doi:10.1007/s12250-015-3676-2

Cited by 6 publications

(7 citation statements)

References 62 publications

(98 reference statements)

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“…9) and acting in an ATP-independent manner, which has been demonstrated for NS in strand displacement experiments (42). Second, the avian reovirus NS protein, which is functionally homologous to mammalian reovirus NS (64, 65), acts as an RNA chaperone in vitro (27), as does the rotavirus NSP2 nonstructural protein (28,63). Third, our cryo-EM analysis demonstrated that NS coats RNAs and forms filamentous structures (Fig.…”

Section: Discussionsupporting

confidence: 60%

“…These results suggest that NS binding to RNA leads to RNA rearrangements allowing the RNA to migrate through the gel matrix. RNA-remodeling proteins that resolve RNA structures are called RNA chaperones (62), which are encoded by some RNA viruses (63). There are three lines of evidence from our study and others suggesting that NS is an RNA chaperone.…”

Section: Discussionmentioning

confidence: 62%

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Reovirus Nonstructural Protein σNS Acts as an RNA Stability Factor Promoting Viral Genome Replication

Zamora

Knowlton

et al. 2018

J Virol

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Viral nonstructural proteins, which are not packaged into virions, are essential for the replication of most viruses. Reovirus, a nonenveloped, double-stranded RNA (dsRNA) virus, encodes three nonstructural proteins that are required for viral replication and dissemination in the host. The reovirus nonstructural protein σNS is a single-stranded RNA (ssRNA)-binding protein that must be expressed in infected cells for production of viral progeny. However, the activities of σNS during individual steps of the reovirus replication cycle are poorly understood. We explored the function of σNS by disrupting its expression during infection using cells expressing a small interfering RNA (siRNA) targeting the σNS-encoding S3 gene and found that σNS is required for viral genome replication. Using complementary biochemical assays, we determined that σNS forms complexes with viral and nonviral RNAs. We also discovered, using and cell-based RNA degradation experiments, that σNS increases the RNA half-life. Cryo-electron microscopy revealed that σNS and ssRNAs organize into long, filamentous structures. Collectively, our findings indicate that σNS functions as an RNA-binding protein that increases the viral RNA half-life. These results suggest that σNS forms RNA-protein complexes in preparation for genome replication. Following infection, viruses synthesize nonstructural proteins that mediate viral replication and promote dissemination. Viruses from the family encode nonstructural proteins that are required for the formation of progeny viruses. Although nonstructural proteins of different viruses in the family diverge in primary sequence, they are functionally homologous and appear to facilitate conserved mechanisms of dsRNA virus replication. Using and cell culture approaches, we found that the mammalian reovirus nonstructural protein σNS binds and stabilizes viral RNA and is required for genome synthesis. This work contributes new knowledge about basic mechanisms of dsRNA virus replication and provides a foundation for future studies to determine how viruses in the family assort and replicate their genomes.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 62%

Reovirus Nonstructural Protein σNS Acts as an RNA Stability Factor Promoting Viral Genome Replication

Zamora

Knowlton

et al. 2018

J Virol

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“…An important group of RNA chaperones are viral nucleocapsid proteins, which facilitate many nucleic-acid-dependent processes in viral life cycles 12–15 . Comparisons among these chaperones reveal very few structural similarities, but many of them are enriched in positively charged and polar residues, resulting in proteins that are known or predicted to be disordered 13,16,17 .…”

Section: Introductionmentioning

confidence: 99%

“…Comparisons among these chaperones reveal very few structural similarities, but many of them are enriched in positively charged and polar residues, resulting in proteins that are known or predicted to be disordered 13,16,17 . Their chaperone activity is present both in vitro and in vivo 3,5,8,12,13 , and the intrinsically disordered regions are both necessary and sufficient for this function 15 . These findings give rise to a question of fundamental importance: How do RNA chaperones function without a well-defined structure?…”

Section: Introductionmentioning

confidence: 99%

Disordered RNA chaperones can enhance nucleic acid folding via local charge screening

et al. 2019

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RNA chaperones are proteins that aid in the folding of nucleic acids, but remarkably, many of these proteins are intrinsically disordered. How can these proteins function without a well-defined three-dimensional structure? Here, we address this question by studying the hepatitis C virus core protein, a chaperone that promotes viral genome dimerization. Using single-molecule fluorescence spectroscopy, we find that this positively charged disordered protein facilitates the formation of compact nucleic acid conformations by acting as a flexible macromolecular counterion that locally screens repulsive electrostatic interactions with an efficiency equivalent to molar salt concentrations. The resulting compaction can bias unfolded nucleic acids towards folding, resulting in faster folding kinetics. This potentially widespread mechanism is supported by molecular simulations that rationalize the experimental findings by describing the chaperone as an unstructured polyelectrolyte.

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“…RNA chaperones are a heterogeneous group of proteins that can destabilize RNA duplexes and promote correct RNA folding in an ATP-independent fashion (20). A wide range of RNA viruses, including flavivirus (21), picornavirus (22), alphavirus (23), coronavirus (24), reovirus (25), iflavirus (26), and alphatetravirus (27), have been found to encode their own RNA helicases and/or RNA chaperones (28).…”

mentioning

confidence: 99%

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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RNA chaperones encoded by RNA viruses

Cited by 6 publications

References 62 publications

Reovirus Nonstructural Protein σNS Acts as an RNA Stability Factor Promoting Viral Genome Replication

Reovirus Nonstructural Protein σNS Acts as an RNA Stability Factor Promoting Viral Genome Replication

Disordered RNA chaperones can enhance nucleic acid folding via local charge screening

Human Norovirus NS3 Has RNA Helicase and Chaperoning Activities

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