V protein, the virulence factor across the family Paramyxoviridae: a review

Tham, May Ling; Yusoff, Khatijah; Othman, Siti Sarah; Chia, Suet Lin

doi:10.35118/apjmbb.2019.027.3.08

Cited by 3 publications

(2 citation statements)

References 86 publications

(154 reference statements)

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“…The successful recovery and subsequent mutation of recombinant viruses such as rAF (456G>T), rAF (624C>T), and rAF (642G>T) could be driven by several factors. Firstly, most of the mutations occurred near the C-terminus of the V protein, which has seven conserved cysteine residues that contribute to pathogenicity and host interferon antagonist activity, as observed in other members of the Paramyxoviridae (Mebatsion et al, 2001;Huang et al, 2003;Park et al, 2003a,b;Qiu et al, 2016;Tham et al, 2019). For instance, mutation of second cysteine to a different amino acid in Nipah virus (NiV) and parainfluenza virus 5 (PIV-5) abolished MDA interference, and substitution of cysteine with alanine at position 189, 207, 214 in mumps virus reduced proteasome-mediated degradation of STAT1 (Kubota et al, 2002;Yokosawa et al, 2002;Ramachandran and Horvath, 2010).…”

Section: Discussionmentioning

confidence: 99%

Site-directed mutagenesis of the C-terminal of the Newcastle disease virus V protein

Tham¹,

Yusoff²,

Othman³

et al. 2022

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Newcastle disease virus (NDV) is a paramyxovirus that is highly pathogenic to poultry causing severe economic loss worldwide. The non-structural V protein is one of the virulence factors of the virus. It antagonises the interferon of the host innate immunity in order to allow successful virus replication in the host cells. However, detailed investigation of recombinant NDV expressing mutated V protein is scarce. In this study, a mesogenic recombinant NDV expressing GFP (rAF-GFP) was used to investigate the relation of V protein mutation on virus pathogenicity. Site-directed mutagenesis was performed using overlapping PCR to introduce four premature stop codons 456G>T, 537G>T, 624C>T and 642G>T in the V gene reading frame. The virus was then rescued and propagated in embryonated chicken eggs. However, instead of the substituted thymine, this nucleotide was mutated into cytosine in three rescued mutants, while 537G>T mutant could not be rescued. As a result, the premature stop codon was substituted with other amino acid and the V protein was expressed in full length. The pathogenicity type of the rAF (456G>T>C), rAF (624C>T>C), and rAF (642G>T>C) mutants remained to be as in mesogenic strains, suggesting that substituted amino acids were functionally interchangeable with the original amino acids present in V protein. It appears that an intact V protein is important for the virus survival. This study explored the possibility of V protein mutation in NDV through exploiting genetic engineering and warrants a further investigation on modifying mutations on a conserved protein in NDV or other paramyxoviruses.

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Section: Discussionmentioning

confidence: 99%

Site-directed mutagenesis of the C-terminal of the Newcastle disease virus V protein

Tham¹,

Yusoff²,

Othman³

et al. 2022

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“…Viral NiV replication therefore occurs intracellularly through post-transcriptional modification, resulting in 5 capping and methylation of RNA. Thereafter, NiV V protein is described as the virulence factor that may abrogate type I IFN responses intracellularly, as we discuss below [49].…”

Section: Nipah Virus Viral Protein Factorsmentioning

confidence: 99%

Immunopathogenesis of Nipah Virus Infection and Associated Immune Responses

Brown¹,

Gravier

Fricke³

et al. 2023

Immuno

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Pandemics in the last two centuries have been initiated by causal pathogens that include Severe Acute Coronavirus 2 (SARS-CoV-2) and Influenza (e.g., the H1N1 pandemic of 2009). The latter is considered to have initiated two prior pandemics in 1918 and 1977, known as the “Spanish Flu” and “Russian Flu”, respectively. Here, we discuss other emerging infections that could be potential public health threats. These include Henipaviruses, which are members of the family Paramyxoviridae that infect bats and other mammals. Paramyxoviridae also include Parainfluenza and Mumps viruses (Rubulavirus) but also Respiratory Syncytial virus (RSV) (Pneumovirus). Additionally included is the Measles virus, recorded for the first time in writing in 1657 (Morbillivirus). In humans and animals, these may cause encephalitis or respiratory diseases. Recently, two more highly pathogenic class 4 viral pathogens emerged. These were named Hendra Henipavirus (HeV) and Nipah Henipavirus (NiV). Nipah virus is a negative-sense single-stranded ribonucleic acid ((−) ssRNA) virus within the family Paramyxoviridae. There are currently no known therapeutics or treatment regimens licensed as effective in humans, with development ongoing. Nipah virus is a lethal emerging zoonotic disease that has been neglected since its characterization in 1999 until recently. Nipah virus infection occurs predominantly in isolated regions of Malaysia, Bangladesh, and India in small outbreaks. Factors that affect animal–human disease transmission include viral mutation, direct contact, amplifying reservoirs, food, close contact, and host cell mutations. There are different strains of Nipah virus, and small outbreaks in humans limit known research and surveillance on this pathogen. The small size of outbreaks in rural areas is suggestive of low transmission. Person-to-person transmission may occur. The role that zoonotic (animal–human) or host immune system cellular factors perform therefore requires analysis. Mortality estimates for NiV infection range from 38–100% (averaging 58.2% in early 2019). It is therefore critical to outline treatments and prevention for NiV disease in future research. The final stages of the disease severely affect key organ systems, particularly the central nervous system and brain. Therefore, here we clarify the pathogenesis, biochemical mechanisms, and all research in context with known immune cell proteins and genetic factors.

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Mechanisms and Consequences of Newcastle Disease Virus W Protein Subcellular Localization in the Nucleus or Mitochondria

Yang

Xue

Xiao

et al. 2021

J Virol

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We previously demonstrated that W proteins from different Newcastle disease virus (NDV) strains localize in either the cytoplasm (e.g., NDV strain SG10) or the nucleus (e.g., NDV strain La Sota). To clarify the mechanism behind these cell localization differences, we overexpressed W protein derived from four different NDV strains or W protein associated with different cellular regions in Vero cells. This revealed that the key region for determining W protein localization is 180–227aa. Further experiments found that there is a nuclear export signal (NES) motif in W protein 211–224aa. W protein could be transported into the nucleus via interaction with KPNA1, KPNA2, and KPNA6 in a nuclear localization signal-dependent manner, and W protein containing an NES was transported back to the cytoplasm in a CRM1-independent manner. Interestingly, we observed that the cytoplasm-localized W protein colocalizes with mitochondria. We rescued the NES-deletion W protein NDV strain rSG10-ΔWC/WΔNES using an NDV reverse genetics system and found that the replication ability, virulence, and pathogenicity of an NDV strain were all higher when the W protein cellular localization was in the nucleus rather than the mitochondria. Further experiments revealed that W protein nuclear localization reduced the expression of IFN-β otherwise stimulated by NDV. Our research reveals the mechanism by which NDV W protein becomes localized to different parts of the cell and demonstrates the outcomes of nuclear or cytoplasmic localization both in vitro and in vivo, laying a foundation for subsequent functional studies of the W protein in NDV and other paramyxoviruses. IMPORTANCE In Newcastle disease virus (NDV), the W protein, like the V protein, is a nonstructural protein encoded by the P gene via RNA editing. Compared with V protein, W protein has a common N-terminal domain but a unique C-terminal domain. V protein is known as a key virulence factor and an important interferon antagonist across the family Paramyxoviridae. In contrast, very little is known about the function of NDV W protein, and this limited information is based on studies of the Nipah virus W protein. Here, we investigated the localization mechanism of NDV W protein and its subcellular distribution in mitochondria. We found that W protein localization differences impact IFN-β production, consequently affecting NDV virulence, replication, and pathogenicity. This work provides new insights on the differential localization mechanism of NDV W proteins, along with fundamental knowledge for understanding the functions of W proteins in NDV and other paramyxoviruses.

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V protein, the virulence factor across the family Paramyxoviridae: a review

Cited by 3 publications

References 86 publications

Site-directed mutagenesis of the C-terminal of the Newcastle disease virus V protein

Site-directed mutagenesis of the C-terminal of the Newcastle disease virus V protein

Immunopathogenesis of Nipah Virus Infection and Associated Immune Responses

Mechanisms and Consequences of Newcastle Disease Virus W Protein Subcellular Localization in the Nucleus or Mitochondria

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