Nucleotide triphosphatase and RNA chaperone activities of murine norovirus NS3

Han, Kang Rok; Lee, Jihye; Kotiguda, Giri Gowda; Jung, Kyoung Ho; Chung, Mi Sook; Kang, Soowon; Hwang, Seungmin; Kim, Kyung Hyun

doi:10.1099/jgv.0.001151

Cited by 10 publications

(5 citation statements)

References 48 publications

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“…While NS1/2 and NS4 are acknowledged to be key main mediators of replication complex formation, NS3, to which RNA chaperon and helicase activities have been attributed [ 96 , 97 ], has also been shown to localise to cellular membranes [ 87 ]. HuNoV and MNV NS3 both induce formation of motile membrane-derived vesicular structures that colocalise with the Golgi apparatus and the endoplasmic reticulum [ 94 , 98 ].…”

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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“…A 2C-like helicase (named NTPase in Figure 2) was identified after the detection of a nucleotide-binding site that is typical for viral proteins (Neill, 1990). Later, this enzyme was shown to be associated with the replication complex and to destabilize double-stranded RNA in an NTP-independent manner, representing an unexpected RNA chaperone-like activity (Li et al, 2017; Han et al, 2018). Thereafter, the p58 cleavage product of the RHDV polyprotein was found to resemble the 3D polymerase of poliovirus, and its role in RNA replication was subsequently confirmed using functional assays (Wirblich et al, 1996; Vazquez et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Calicivirus RNA-Dependent RNA Polymerases: Evolution, Structure, Protein Dynamics, and Function

et al. 2019

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The Caliciviridae are viruses with a positive-sense, single-stranded RNA genome that is packaged into an icosahedral, environmentally stable protein capsid. The family contains five genera ( Norovirus , Nebovirus, Sapovirus , Lagovirus , and Vesivirus ) that infect vertebrates including amphibians, reptiles, birds, and mammals. The RNA-dependent RNA polymerase (RdRp) replicates the genome of RNA viruses and can speed up evolution due to its error-prone nature. Studying calicivirus RdRps in the context of genuine virus replication is often hampered by a lack of suitable model systems. Enteric caliciviruses and RHDV in particular are notoriously difficult to propagate in cell culture; therefore, molecular studies of replication mechanisms are challenging. Nevertheless, research on recombinant proteins has revealed several unexpected characteristics of calicivirus RdRps. For example, the RdRps of RHDV and related lagoviruses possess the ability to expose a hydrophobic motif, to rearrange Golgi membranes, and to copy RNA at unusually high temperatures. This review is focused on the structural dynamics, biochemical properties, kinetics, and putative interaction partners of these RdRps. In addition, we discuss the possible existence of a conserved but as yet undescribed structural element that is shared amongst the RdRps of all caliciviruses.

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“…These findings strongly suggest that the function domain (1-179 aa) is important for NTPase-mediated inhibition of IFN-β production. HuNoV NTPase plays an important role in RNA synthesis in vitro (Pfister and Wimmer, 2001;Han et al, 2018;Li et al, 2018) and contains motifs A (GI HuNoV NTPase 162-169 aa), B (GI HuNoV NTPase 212 and 213 aa), and C (257-260 aa) relating to NTPase activity (Liu et al, 1996;Li et al, 2018). Mutations in motif A, B, or C abolished NTPase activity (Pfister and Wimmer, 1999).…”

Section: Discussionmentioning

confidence: 99%

Human Norovirus NTPase Antagonizes Interferon-β Production by Interacting With IkB Kinase ε

Zheng

Zhang

et al. 2021

Front. Microbiol.

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Human norovirus (HuNoV) is the leading cause of epidemic acute gastroenteritis worldwide. Type I interferons (IFN)-α/β are highly potent cytokines that are initially identified for their essential roles in antiviral defense. It was reported that HuNoV infection did not induce IFN-β expression but was controlled in the presence of IFN-β in human intestinal enteroids and a gnotobiotic pig model, suggesting that HuNoV has likely developed evasion countermeasures. In this study, we found that a cDNA clone of GII.4 HuNoV, the predominantly circulating genotype worldwide, inhibits the production of IFN-β and identified the viral NTPase as a key component responsible for such inhibition. HuNoV NTPase not only inhibits the activity of IFN-β promoter but also the mRNA and protein production of IFN-β. Additional studies indicate that NTPase inhibits the phosphorylation and nuclear translocation of interferon-regulatory factor-3 (IRF-3), leading to the suppression of IFN-β promoter activation. Mechanistically, NTPase interacts with IkB kinase ε (IKKε), an important factor for IRF-3 phosphorylation, and such interaction blocks the association of IKKε with unanchored K48-linked polyubiquitin chains, resulting in the inhibition of IKKε phosphorylation. Further studies demonstrated that the 1-179 aa domain of NTPase which interacts with IKKε is critical for the suppression of IFN-β production. Our findings highlight the role of HuNoV NTPase in the inhibition of IFN-β production, providing insights into a novel mechanism underlying how HuNoV evades the host innate immunity.

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Nucleotide triphosphatase and RNA chaperone activities of murine norovirus NS3

Cited by 10 publications

References 48 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

Calicivirus RNA-Dependent RNA Polymerases: Evolution, Structure, Protein Dynamics, and Function

Human Norovirus NTPase Antagonizes Interferon-β Production by Interacting With IkB Kinase ε

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