The ORF4b-encoded accessory proteins of Middle East respiratory syndrome coronavirus and two related bat coronaviruses localize to the nucleus and inhibit innate immune signalling

Matthews, Krystal; Coleman, Christopher M.; Meer, Yvonne van der; Snijder, Eric J.; Frieman, Matthew B.

doi:10.1099/vir.0.062059-0

Cited by 105 publications

(141 citation statements)

References 34 publications

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“…p3 and p5 have been found in the ERGIC, whereas p4a and p4b display a diffuse cytoplasmic distribution and are also partly localized to the nucleus (Siu et al, 2014), although in another study, p4b was found to localize exclusively to the nucleus (Matthews et al, 2014). Both the p4a and the p4b protein of MERS coronavirus have been shown to be a type-I interferon antagonists (Siu et al, 2014;Matthews et al, 2014;Niemeyer et al, 2013). The p4a is particularly interesting in this context, as it is a Table 7 SARS Co-V ORF9b.…”

Section: Accessory Proteins Of Other Betacoronavirusesmentioning

confidence: 97%

Accessory proteins of SARS-CoV and other coronaviruses

et al. 2014

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The huge RNA genome of SARS coronavirus comprises a number of open reading frames that code for a total of eight accessory proteins. Although none of these are essential for virus replication, some appear to have a role in virus pathogenesis. Notably, some SARS-CoV accessory proteins have been shown to modulate the interferon signaling pathways and the production of pro-inflammatory cytokines. The structural information on these proteins is also limited, with only two (p7a and p9b) having their structures determined by X-ray crystallography. This review makes an attempt to summarize the published knowledge on SARS-CoV accessory proteins, with an emphasis on their involvement in virus-host interaction. The accessory proteins of other coronaviruses are also briefly discussed. This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses" (see Introduction by Hilgenfeld and Peiris (2013)).

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Section: Accessory Proteins Of Other Betacoronavirusesmentioning

confidence: 97%

Accessory proteins of SARS-CoV and other coronaviruses

et al. 2014

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“…Following nuclear localization, SARS-CoV 3b protein traffics to the outer membrane of mitochondria, where it inhibits the induction of type 1 interferon (IFN) elicited by RIG-I and the mitochondrial antiviral signaling protein (77). Similarly, the 4b proteins of MERS-CoV, bat coronavirus (BtCoV)-HKU4, and BtCoV-HKU5 also localize to the nucleus and inhibit type 1 IFN induction and, less efficiently, NF-κB signaling pathways (78). …”

Section: Relevance Of the Cell Nucleus In Coronavirus Rna Synthesismentioning

confidence: 99%

Continuous and Discontinuous RNA Synthesis in Coronaviruses

et al. 2015

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Replication of the coronavirus genome requires continuous RNA synthesis, whereas transcription is a discontinuous process unique among RNA viruses. Transcription includes a template switch during the synthesis of subgenomic negative-strand RNAs to add a copy of the leader sequence. Coronavirus transcription is regulated by multiple factors, including the extent of base-pairing between transcription-regulating sequences of positive and negative polarity, viral and cell protein–RNA binding, and high-order RNA-RNA interactions. Coronavirus RNA synthesis is performed by a replication-transcription complex that includes viral and cell proteins that recognize cis-acting RNA elements mainly located in the highly structured 5′ and 3′ untranslated regions. In addition to many viral nonstructural proteins, the presence of cell nuclear proteins and the viral nucleocapsid protein increases virus amplification efficacy. Coronavirus RNA synthesis is connected with the formation of double-membrane vesicles and convoluted membranes. Coronaviruses encode proofreading machinery, unique in the RNA virus world, to ensure the maintenance of their large genome size.

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“…Several downstream open reading frames like ORF3a, ORF3b and ORF6 also antagonize sensing or signaling pathways, or block karyopherin 2 nuclear import [13,21] (Figure 1). MERS-CoV also encodes several luxury functions with interferon antagonism activities, including ORF4a, ORF4b and perhaps ORF5, noting that ORF4b antagonizes phosphodiesterase activity and RNAse L activation [26,27,28,29,30]. However, how the exact underlying mechanisms allow these antagonistic molecules to interfere with the effector molecules that establish an antiviral state, assist in wound repair, or prime and enhance an adaptive immune response, which is critical for clearance, is still under study.…”

Section: Innate Immunity and Coronavirus Infectionsmentioning

confidence: 99%

Epigenetic Landscape during Coronavirus Infection

2017

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Coronaviruses (CoV) comprise a large group of emerging human and animal pathogens, including the highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) strains. The molecular mechanisms regulating emerging coronavirus pathogenesis are complex and include virus–host interactions associated with entry, replication, egress and innate immune control. Epigenetics research investigates the genetic and non-genetic factors that regulate phenotypic variation, usually caused by external and environmental factors that alter host expression patterns and performance without any change in the underlying genotype. Epigenetic modifications, such as histone modifications, DNA methylation, chromatin remodeling, and non-coding RNAs, function as important regulators that remodel host chromatin, altering host expression patterns and networks in a highly flexible manner. For most of the past two and a half decades, research has focused on the molecular mechanisms by which RNA viruses antagonize the signaling and sensing components that regulate induction of the host innate immune and antiviral defense programs upon infection. More recently, a growing body of evidence supports the hypothesis that viruses, even lytic RNA viruses that replicate in the cytoplasm, have developed intricate, highly evolved, and well-coordinated processes that are designed to regulate the host epigenome, and control host innate immune antiviral defense processes, thereby promoting robust virus replication and pathogenesis. In this article, we discuss the strategies that are used to evaluate the mechanisms by which viruses regulate the host epigenome, especially focusing on highly pathogenic respiratory RNA virus infections as a model. By combining measures of epigenome reorganization with RNA and proteomic datasets, we articulate a spatial-temporal data integration approach to identify regulatory genomic clusters and regions that play a crucial role in the host’s innate immune response, thereby defining a new viral antagonism mechanism following emerging coronavirus infection.

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The ORF4b-encoded accessory proteins of Middle East respiratory syndrome coronavirus and two related bat coronaviruses localize to the nucleus and inhibit innate immune signalling

Cited by 105 publications

References 34 publications

Accessory proteins of SARS-CoV and other coronaviruses

Accessory proteins of SARS-CoV and other coronaviruses

Continuous and Discontinuous RNA Synthesis in Coronaviruses

Epigenetic Landscape during Coronavirus Infection

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