Expression of the NS5 (VPg) Protein of Murine Norovirus Induces a G1/S Phase Arrest

Davies, Colin; Ward, Vernon K.

doi:10.1371/journal.pone.0161582

Cited by 11 publications

(16 citation statements)

References 43 publications

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“…PYCR1 leads to cell cycle arrest [104,105]. A similar mechanism has been shown for the murine NoV VPg [106]. It remains unknown if VPg directs cell cycle arrest through PYCR1 downregulation.…”

Section: Discussionsupporting

confidence: 56%

Vero Cells as a Mammalian Cell Substrate for Human Norovirus

Todd

Tripp

2020

Viruses

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Human norovirus (HuNoV) is a principal cause of acute gastroenteritis worldwide, particularly in developing countries. Its global prevalence is underscored by more serious morbidity and some mortality in the young (<5 years) and the elderly. To date, there are no licensed vaccines or approved therapeutics for HuNoV, mostly because there are limited cell culture systems and small animal models available. Recently described cell culture systems are not ideal substrates for HuNoV vaccine development because they are not clonal or only support a single strain. In this study, we show Vero cell-based replication of two pandemic GII.4 HuNoV strains and one GII.3 strain and confirm exosome-mediated HuNoV infection in Vero cells. Lastly, we show that trypsin addition to virus cultures or disruption of Vero cell host genes can modestly increase HuNoV replication. These data provide support for Vero cells as a cell culture model for HuNoV.

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Section: Discussionsupporting

confidence: 56%

Vero Cells as a Mammalian Cell Substrate for Human Norovirus

Todd

Tripp

2020

Viruses

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“…Cell cycle modification is an adventitious strategy of viruses to promote replication and transmission(76). MNV has also been shown to induce a G 0 /G 1 cell cycle arrest which is at least partially dependent on the viral protein VPg in RAW cells(19, 77). Davies et al reports Affymetrix data from 18 h p.i.…”

Section: Discussionmentioning

confidence: 99%

Comparative Transcriptomic Response of Primary and Immortalized Macrophages to Murine Norovirus Infection

Levenson

Martens

Kanakabandi

et al. 2018

The Journal of Immunology

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Murine norovirus (NoV) is genetically similar to human NoV and offers both an efficient in vitro cell culture system and an animal model by which to investigate the molecular basis of replication. In this study, we present a detailed global view of host alterations to cellular pathways that occur during the progression of a NoV infection. This was accomplished for both BALB/c-derived RAW264.7 (RAW) cells, an immortalized cell line widely used in in vitro replication studies, and primary bone marrow-derived macrophages (BMDM), representing a permissive in vivo target cell in the host. Murine NoV replicated in both cell types, although detected genome copies were approximately one log lower in BMDM compared with RAW cells. RAW and BMDM cells shared an IRF3/7-based IFN response that occurred early in infection. In RAW cells, transcriptional upregulation and INF-β expression were not coupled in that a significant delay in the detection of secreted INF-β was observed. In contrast, primary BMDM showed an early upregulation of transcripts and immediate release of INF-β that might account for lower virus yield. Differences in the transcriptional pathway responses included a marked decrease in expression of key genes in the cell cycle and lipid pathways in RAW cells compared with that of BMDM. Our comparative analysis indicates the existence of varying host responses to virus infection in populations of permissive cells. Awareness of these differences at the gene level will be important in the application of a given permissive culture system to the study of NoV immunity, pathogenesis, and drug development.

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“…Recently, it was shown that infection of a macrophage cell line with MNV results in a G0/G1 cell cycle arrest, and that expression of MNV viral protein genome-linked (VPg) alone is sufficient to induce the arrest [16,17]. MNV VPg is a multi-functional protein required for several important functions within the cell, including genome replication and viral protein translation.…”

Section: Introductionmentioning

confidence: 99%

“…Substitution of Y26 with an alanine (Y26A) prevents the interaction of MNV VPg with viral RNA [18,20]. In the context of the cell cycle, a Y26A mutation has no effect on G0/G1 accumulation, suggesting that the cell cycle arrest does not require attachment of MNV VPg to the viral RNA [16]. A second, well-characterized function of MNV VPg is to recruit host eukaryotic initiation factors (eIFs) for preferential translation of the viral genome during infection [21,22].…”

Section: Introductionmentioning

confidence: 99%

Cell Cycle Arrest is a Conserved Function of Norovirus VPg Proteins

McSweeney

Davies

Ward

2019

Viruses

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Murine norovirus (MNV) viral protein genome-linked (VPg) manipulates the cell cycle to induce a G0/G1 arrest and gain a beneficial replication environment. All viruses of the norovirus genus encode a VPg protein; however, it is unknown if the G0/G1 arrest induced by MNV VPg is conserved in other members of the genus. RNA transcripts encoding a representative viral VPg from five norovirus genogroups were transfected into RAW-Blue murine macrophages, and the percentage of cells in each phase of the cell cycle was determined. A G0/G1 cell cycle arrest was observed for all norovirus VPg proteins tested, and in the wider Caliciviridae family the arrest was also conserved in rabbit hemorrhagic disease virus (RHDV) VPg and human sapovirus (HuSV) VPg. Truncation of MNV VPg shows that the first 62 amino acids are sufficient for a cell cycle arrest, and alignment of VPg sequences revealed a conserved motif in the N-terminal region of VPg. Analysis of VPg constructs with single N-terminal region point mutations, or exchange of N-terminal regions between VPg proteins, confirmed the importance of the N-terminal region for cell cycle arrest. These results provide evidence that G0/G1 cell cycle arrest is a conserved function of norovirus VPg proteins that involves the N-terminal region of these proteins.

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Expression of the NS5 (VPg) Protein of Murine Norovirus Induces a G1/S Phase Arrest

Cited by 11 publications

References 43 publications

Vero Cells as a Mammalian Cell Substrate for Human Norovirus

Vero Cells as a Mammalian Cell Substrate for Human Norovirus

Comparative Transcriptomic Response of Primary and Immortalized Macrophages to Murine Norovirus Infection

Cell Cycle Arrest is a Conserved Function of Norovirus VPg Proteins

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