Cell Cycle Arrest is a Conserved Function of Norovirus VPg Proteins

McSweeney, Alice M.; Davies, Colin; Ward, Vernon K.

doi:10.3390/v11030217

Cited by 9 publications

(11 citation statements)

References 36 publications

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“…Then, the negative-sense genomic and subgenomic RNAs are used as templates for the synthesis of positive sense genomic and subgenomic RNAs [ 21 ]. These transcription reactions are catalysed by the RNA-dependent RNA-polymerase (RdRp, NS7), using de novo mechanisms for synthesis of negative-stranded RNA [ 99 , 100 ], and VPg-dependent mechanisms of positive sense genomic and subgenomic RNA synthesis in which the NS7 uses multifunctional VPg as a proteinaceous primer [ 23 , 25 , 101 ]. Multifunctional VPg [ 24 ] plays various roles in norovirus replication including induction of higher-order RdRp multimer or tubular fibril formation and enhancement of MNV RdRp activity [ 25 ].…”

Section: Replicative Cyclementioning

confidence: 99%

Noroviruses—The State of the Art, Nearly Fifty Years after Their Initial Discovery

Ludwig‐Begall

Mauroy

Thiry

2021

Viruses

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Human noroviruses are recognised as the major global cause of viral gastroenteritis. Here, we provide an overview of notable advances in norovirus research and provide a short recap of the novel model systems to which much of the recent progress is owed. Significant advances include an updated classification system, the description of alternative virus-like protein morphologies and capsid dynamics, and the further elucidation of the functions and roles of various viral proteins. Important milestones include new insights into cell tropism, host and microbial attachment factors and receptors, interactions with the cellular translational apparatus, and viral egress from cells. Noroviruses have been detected in previously unrecognised hosts and detection itself is facilitated by improved analytical techniques. New potential transmission routes and/or viral reservoirs have been proposed. Recent in vivo and in vitro findings have added to the understanding of host immunity in response to norovirus infection, and vaccine development has progressed to preclinical and even clinical trial testing. Ongoing development of therapeutics includes promising direct-acting small molecules and host-factor drugs.

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Section: Replicative Cyclementioning

confidence: 99%

Noroviruses—The State of the Art, Nearly Fifty Years after Their Initial Discovery

Ludwig‐Begall

Mauroy

Thiry

2021

Viruses

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“…Furthermore, it was identified that the cell cycle arrest is induced by the conserved motif KGKxKxGRG in the N-terminal region which is found in the VPg proteins of all the norovirus genogroups, except for GIII. These findings demonstrate that the N-terminal end of VPg is essential to arrest the cell cycle in G1/G0 and promotes HuNoV replication (69). Therefore, the interactions of VPg with the RdRp and cellular components of the host play an important role in the viral replicative cycle and the pathogenesis of HuNoV.…”

Section: Vpgmentioning

confidence: 76%

Human Norovirus Proteins: Implications in the Replicative Cycle, Pathogenesis, and the Host Immune Response

et al. 2020

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Human noroviruses (HuNoVs) are the cause of more than 95% of epidemic non-bacterial gastroenteritis worldwide, with some lethal cases. These viral agents affect people of all ages. However, young children and older adults are the highest-risk groups, being affected with the greatest rate of hospitalizations and morbidity cases. HuNoV structural proteins, especially VP1, have been studied extensively. In contrast, the functions of the non-structural proteins of the virus have been undescribed in depth. Studies on HuNoV non-structural proteins have mostly been made by expressing them individually in in vitro cultures, providing insights of their functions and the role that they play in HuNoV replication and pathogenesis. This review examines exhaustively the functions of both HuNoV structural and non-structural proteins and their possible role within the viral replicative cycle and the pathogenesis of the virus. It also highlights recent findings regarding the host's innate and adaptive immune responses against HuNoV, which are of great relevance for diagnostics and vaccine development so as to prevent infections caused by these fastidious viruses.

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Section: Resultsmentioning

confidence: 99%

“…The conserved N-terminal region of norovirus VPg proteins is involved in binding of NTPs, nucleotidylation, and cell cycle manipulation [ 11 , 17 , 25 ]. We were interested in determining if mutations that eliminate RNA binding have any effect on the cell cycle, as previously this has only been investigated in relation to single point mutations or truncations of the motif [ 17 ]. To determine the importance of positively charged amino acids for a G0/G1 cell cycle arrest, mRNA transcripts encoding MNV VPg TM and MNV VPg K2-12 were transfected into asynchronous RAW-Blue cells and the percentage of cells in each phase of the cell cycle measured by flow cytometry ( Figure 9 ).…”

Section: Resultsmentioning

confidence: 99%

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Norovirus VPg Binds RNA through a Conserved N-Terminal K/R Basic Patch

McSweeney

Young

Ward

2021

Viruses

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The viral protein genome-linked (VPg) of noroviruses is a multi-functional protein that participates in essential roles during the viral replication cycle. Predictive analyses indicate that murine norovirus (MNV) VPg contains a disordered N-terminal region with RNA binding potential. VPg proteins were expressed with an N-terminal spidroin fusion protein in insect cells and the interaction with RNA investigated by electrophoretic mobility shift assays (EMSA) against a series of RNA probes (pentaprobes) representing all possible five nucleotide combinations. MNV VPg and human norovirus (HuNV) VPg proteins were directly bound to RNA in a non-specific manner. To identify amino acids involved in binding to RNA, all basic (K/R) residues in the first 12 amino acids of MNV VPg were mutated to alanine. Removal of the K/R amino acids eliminated RNA binding and is consistent with a K/R basic patch RNA binding motif within the disordered N-terminal region of norovirus VPgs. Finally, we show that mutation of the K/R basic patch required for RNA binding eliminates the ability of MNV VPg to induce a G0/G1 cell cycle arrest.

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Cell Cycle Arrest is a Conserved Function of Norovirus VPg Proteins

Cited by 9 publications

References 36 publications

Noroviruses—The State of the Art, Nearly Fifty Years after Their Initial Discovery

Noroviruses—The State of the Art, Nearly Fifty Years after Their Initial Discovery

Human Norovirus Proteins: Implications in the Replicative Cycle, Pathogenesis, and the Host Immune Response

Norovirus VPg Binds RNA through a Conserved N-Terminal K/R Basic Patch

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