scholarly journals Paramyxovirus V Proteins Interact with the RIG-I/TRIM25 Regulatory Complex and Inhibit RIG-I Signaling

2018 ◽  
Vol 92 (6) ◽  
Author(s):  
Maria T. Sánchez-Aparicio ◽  
Leighland J. Feinman ◽  
Adolfo García-Sastre ◽  
Megan L. Shaw
Keyword(s):  
Signaling Pathway ◽  
Measles Virus ◽  
Sendai Virus ◽  
Regulatory Protein ◽  
Nipah Virus ◽  
Antiviral Signaling ◽  
V Protein ◽  
Protein Functions ◽  
Regulatory Complex ◽  
Mitochondrial Antiviral Signaling

ABSTRACT Paramyxovirus V proteins are known antagonists of the RIG-I-like receptor (RLR)-mediated interferon induction pathway, interacting with and inhibiting the RLR MDA5. We report interactions between the Nipah virus V protein and both RIG-I regulatory protein TRIM25 and RIG-I. We also observed interactions between these host proteins and the V proteins of measles virus, Sendai virus, and parainfluenza virus. These interactions are mediated by the conserved C-terminal domain of the V protein, which binds to the tandem caspase activation and recruitment domains (CARDs) of RIG-I (the region of TRIM25 ubiquitination) and to the SPRY domain of TRIM25, which mediates TRIM25 interaction with the RIG-I CARDs. Furthermore, we show that V interaction with TRIM25 and RIG-I prevents TRIM25-mediated ubiquitination of RIG-I and disrupts downstream RIG-I signaling to the mitochondrial antiviral signaling protein. This is a novel mechanism for innate immune inhibition by paramyxovirus V proteins, distinct from other known V protein functions such as MDA5 and STAT1 antagonism. IMPORTANCE The host RIG-I signaling pathway is a key early obstacle to paramyxovirus infection, as it results in rapid induction of an antiviral response. This study shows that paramyxovirus V proteins interact with and inhibit the activation of RIG-I, thereby interrupting the antiviral signaling pathway and facilitating virus replication.

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

2019 ◽  
pp. 73-85
Author(s):  
May Ling Tham ◽  
Khatijah Yusoff ◽  
Sarah Othman ◽  
Suet Lin Chia
Keyword(s):  
Measles Virus ◽  
Sendai Virus ◽  
Nipah Virus ◽  
Host Cells ◽  
V Protein ◽  
Signal Transducers ◽  
Stat Proteins ◽  
Animal Pathogens ◽  
The Family ◽  
Interferon Antagonists

Paramyxoviridae is a family of viruses within the order Mononegavirales and comprises 14 genera; Metaavulavirus, Orthoavulavirus, Paraavulavirus, Synodonvirus, Ferlavirus, Aquaparamyxovirus, Henipavirus, Morbillivirus, Respirovirus, Jeilongvirus, Narmovirus, Salemvirus, Pararubulavirus and Orthorubulavirus. The members within this family are negative and single-stranded RNA viruses including human and animal pathogens such as measles virus (MeV), Nipah virus (NiV), mumps virus (MuV), Sendai virus (SeV) and Newcastle disease virus (NDV). The V protein is conserved within the family and plays an essential role in viral pathogenicity. Although V proteins of many paramyxoviruses are interferon-antagonists which counteract with the host’s innate immunity, there are still differences in the mode of action of the V protein between different genera or species within the same genera. The strategies to circumvent the host interferon (IFN) pathway can be divided into three general mechanisms; degradation of signal transducers and activators of transcription (STAT) protein, inhibition of phosphorylation of the transcription factor and, inhibition of translocation of STAT proteins into the nucleus. As a result, inhibition of IFN signalling and production promotes viral replication in the host cells. This review highlights the mechanism of the paramyxoviral V protein in evading the host IFN system.

scholarly journals Structure and assembly of double-headed Sendai virus nucleocapsids

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Na Zhang ◽  
Hong Shan ◽  
Mingdong Liu ◽  
Tianhao Li ◽  
Rui Luo ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Measles Virus ◽  
Sendai Virus ◽  
Nipah Virus ◽  
Mumps Virus ◽  
Genome Replication ◽  
Direct Visualization ◽  
Closed State ◽  
Cryo Electron Microscopy ◽  
Negative Sense

AbstractParamyxoviruses, including the mumps virus, measles virus, Nipah virus and Sendai virus (SeV), have non-segmented single-stranded negative-sense RNA genomes which are encapsidated by nucleoproteins into helical nucleocapsids. Here, we reported a double-headed SeV nucleocapsid assembled in a tail-to-tail manner, and resolved its helical stems and clam-shaped joint at the respective resolutions of 2.9 and 3.9 Å, via cryo-electron microscopy. Our structures offer important insights into the mechanism of the helical polymerization, in particular via an unnoticed exchange of a N-terminal hole formed by three loops of nucleoproteins, and unveil the clam-shaped joint in a hyper-closed state for nucleocapsid dimerization. Direct visualization of the loop from the disordered C-terminal tail provides structural evidence that C-terminal tail is correlated to the curvature of nucleocapsid and links nucleocapsid condensation and genome replication and transcription with different assembly forms.

scholarly journals Sendai Virus V Protein Inhibits the Secretion of Interleukin-1β by Preventing NLRP3 Inflammasome Assembly

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Takayuki Komatsu ◽  
Yukie Tanaka ◽  
Yoshinori Kitagawa ◽  
Naoki Koide ◽  
Yoshikazu Naiki ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Sendai Virus ◽  
Nipah Virus ◽  
Innate Immune ◽  
Parainfluenza Virus ◽  
Inflammasome Activation ◽  
V Protein ◽  
Nlrp3 Inflammasome Activation ◽  
Human Parainfluenza Virus

ABSTRACT Inflammasomes play a key role in host innate immune responses to viral infection by caspase-1 (Casp-1) activation to facilitate interleukin-1β (IL-1β) secretion, which contributes to the host antiviral defense. The NLRP3 inflammasome consists of the cytoplasmic sensor molecule NLRP3, adaptor protein ASC, and effector protein pro-caspase-1 (pro-Casp-1). NLRP3 and ASC promote pro-Casp-1 cleavage, leading to IL-1β maturation and secretion. However, as a countermeasure, viral pathogens have evolved virulence factors to antagonize inflammasome pathways. Here we report that V gene knockout Sendai virus [SeV V(−)] induced markedly greater amounts of IL-1β than wild-type SeV in infected THP1 macrophages. Deficiency of NLRP3 in cells inhibited SeV V(−)-induced IL-1β secretion, indicating an essential role for NLRP3 in SeV V(−)-induced IL-1β activation. Moreover, SeV V protein inhibited the assembly of NLRP3 inflammasomes, including NLRP3-dependent ASC oligomerization, NLRP3-ASC association, NLRP3 self-oligomerization, and intermolecular interactions between NLRP3 molecules. Furthermore, a high correlation between the NLRP3-binding capacity of V protein and the ability to block inflammasome complex assembly was observed. Therefore, SeV V protein likely inhibits NLRP3 self-oligomerization by interacting with NLRP3 and inhibiting subsequent recruitment of ASC to block NLRP3-dependent ASC oligomerization, in turn blocking full activation of the NLRP3 inflammasome and thus blocking IL-1β secretion. Notably, the inhibitory action of SeV V protein on NLRP3 inflammasome activation is shared by other paramyxovirus V proteins, such as Nipah virus and human parainfluenza virus type 2. We thus reveal a mechanism by which paramyxovirus inhibits inflammatory responses by inhibiting NLRP3 inflammasome complex assembly and IL-1β activation. IMPORTANCE The present study demonstrates that the V protein of SeV, Nipah virus, and human parainfluenza virus type 2 interacts with NLRP3 to inhibit NLRP3 inflammasome activation, potentially suggesting a novel strategy by which viruses evade the host innate immune response. As all members of the Paramyxovirinae subfamily carry similar V genes, this new finding may also lead to identification of novel therapeutic targets for paramyxovirus infection and related diseases.

scholarly journals Control of Nipah Virus Infection in Mice by the Host Adaptors Mitochondrial Antiviral Signaling Protein (MAVS) and Myeloid Differentiation Primary Response 88 (MyD88)

2019 ◽  
Vol 221 (Supplement_4) ◽  
pp. S401-S406 ◽  
Author(s):  
Mathieu Iampietro ◽  
Noemie Aurine ◽  
Kevin P Dhondt ◽  
Claire Dumont ◽  
Rodolphe Pelissier ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Critical Role ◽  
Nipah Virus ◽  
Primary Response ◽  
Myeloid Differentiation ◽  
Type I ◽  
Antiviral Signaling ◽  
Signaling Protein ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

Abstract Interferon (IFN) type I plays a critical role in the protection of mice from lethal Nipah virus (NiV) infection, but mechanisms responsible for IFN-I induction remain unknown. In the current study, we demonstrated the critical role of the mitochondrial antiviral signaling protein signaling pathway in IFN-I production and NiV replication in murine embryonic fibroblasts in vitro, and the redundant but essential roles of both mitochondrial antiviral signaling protein and myeloid differentiation primary response 88 adaptors, but not toll/interleukin-1 receptor/resistance [TIR] domain–containing adaptor–inducing IFN-β (TRIF), in the control of NiV infection in mice. These results reveal potential novel targets for antiviral intervention and help in understanding NiV immunopathogenesis.

scholarly journals Newcastle Disease Virus V Protein Degrades Mitochondrial Antiviral Signaling Protein To Inhibit Host Type I Interferon Production via E3 Ubiquitin Ligase RNF5

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
Yingjie Sun ◽  
Hang Zheng ◽  
Shengqing Yu ◽  
Yunlei Ding ◽  
Wei Wu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Newcastle Disease Virus ◽  
Ubiquitin Ligase ◽  
Newcastle Disease ◽  
E3 Ubiquitin Ligase ◽  
The Other ◽  
Antiviral Signaling ◽  
V Protein ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

ABSTRACTParamyxovirus establishes an intimate and complex interaction with the host cell to counteract the antiviral responses elicited by the cell. Of the various pattern recognition receptors in the host, the cytosolic RNA helicases interact with viral RNA to activate the mitochondrial antiviral signaling protein (MAVS) and subsequent cellular interferon (IFN) response. On the other hand, viruses explore multiple strategies to resist host immunity. In this study, we found that Newcastle disease virus (NDV) infection induced MAVS degradation. Further analysis showed that NDV V protein degraded MAVS through the ubiquitin-proteasome pathway to inhibit IFN-β production. Moreover, NDV V protein led to proteasomal degradation of MAVS through Lys362 and Lys461 ubiquitin to prevent IFN production. Further studies showed that NDV V protein recruited E3 ubiquitin ligase RNF5 to polyubiquitinate and degrade MAVS. Compared with levels for wild-type NDV infection, V-deficient NDV induced attenuated MAVS degradation and enhanced IFN-β production at the late stage of infection. Several other paramyxovirus V proteins showed activities of degrading MAVS and blocking IFN production similar to those of NDV V protein. The present study revealed a novel role of NDV V protein in targeting MAVS to inhibit cellular IFN production, which reinforces the fact that the virus orchestrates the cellular antiviral response to its own benefit.IMPORTANCEHost anti-RNA virus innate immunity relies mainly on the recognition by retinoic acid-inducible gene I and melanoma differentiation-associated protein 5 and subsequently initiates downstream signaling through interaction with MAVS. On the other hand, viruses have developed various strategies to counteract MAVS-mediated signaling. The mechanism for paramyxoviruses regulating MAVS to benefit their infection remains unknown. In this article, we demonstrate that the V proteins of NDV and several other paramyxoviruses target MAVS for ubiquitin-mediated degradation through E3 ubiquitin ligase RING-finger protein 5 (RNF5). MAVS degradation leads to the inhibition of the downstream IFN-β pathway and therefore benefits virus proliferation. Our study reveals a novel mechanism of NDV evading host innate immunity and provides insight into the therapeutic strategies for the control of paramyxovirus infection.

scholarly journals A Shared Interface Mediates Paramyxovirus Interference with Antiviral RNA Helicases MDA5 and LGP2

2009 ◽  
Vol 83 (14) ◽  
pp. 7252-7260 ◽  
Author(s):  
Jean-Patrick Parisien ◽  
Darja Bamming ◽  
Akihiko Komuro ◽  
Aparna Ramachandran ◽  
Jason J. Rodriguez ◽  
...  
Keyword(s):  
Virus Type ◽  
Measles Virus ◽  
Atp Hydrolysis ◽  
Nipah Virus ◽  
Rna Helicase ◽  
Hendra Virus ◽  
Parainfluenza Virus ◽  
Rna Helicases ◽  
V Protein ◽  
Mechanistic Basis

ABSTRACT Diverse members of the Paramyxovirus family of negative-strand RNA viruses effectively suppress host innate immune responses through the actions of their V proteins. The V protein mediates interference with the interferon regulatory RNA helicase MDA5 to avoid cellular antiviral responses. Analysis of the interaction interface revealed the MDA5 helicase C domain as necessary and sufficient for association with V proteins from human parainfluenza virus type 2, parainfluenza virus type 5, measles virus, mumps virus, Hendra virus, and Nipah virus. The identified ∼130-residue region is highly homologous between MDA5 and the related antiviral helicase LGP2, but not RIG-I. Results indicate that the paramyxovirus V proteins can also associate with LGP2. The V protein interaction was found to disrupt ATP hydrolysis mediated by both MDA5 and LGP2. These findings provide a potential mechanistic basis for V protein-mediated helicase interference and identify LGP2 as a second cellular RNA helicase targeted by paramyxovirus V proteins.

scholarly journals Dissociation of Paramyxovirus Interferon Evasion Activities: Universal and Virus-Specific Requirements for Conserved V Protein Amino Acids in MDA5 Interference

2010 ◽  
Vol 84 (21) ◽  
pp. 11152-11163 ◽  
Author(s):  
Aparna Ramachandran ◽  
Curt M. Horvath
Keyword(s):  
Measles Virus ◽  
Nipah Virus ◽  
Site Directed Mutagenesis ◽  
Helicase Domain ◽  
Protein Chain ◽  
Conserved Residues ◽  
V Protein ◽  
Protein Protein Interaction ◽  
Terminal Domain ◽  
Amino Acid Region

ABSTRACT The V protein of the paramyxovirus subfamily Paramyxovirinae is an important virulence factor that can interfere with host innate immunity by inactivating the cytosolic pathogen recognition receptor MDA5. This interference is a result of a protein-protein interaction between the highly conserved carboxyl-terminal domain of the V protein and the helicase domain of MDA5. The V protein C-terminal domain (CTD) is an evolutionarily conserved 49- to 68-amino-acid region that coordinates two zinc atoms per protein chain. Site-directed mutagenesis of conserved residues in the V protein CTD has revealed both universal and virus-specific requirements for zinc coordination in MDA5 engagement and has also identified other conserved residues as critical for MDA5 interaction and interference. Mutation of these residues produces V proteins that are specifically defective for MDA5 interference and not impaired in targeting STAT1 for proteasomal degradation via the VDC ubiquitin ligase complex. Results demonstrate that mutation of conserved charged residues in the V proteins of Nipah virus, measles virus, and mumps virus also abolishes MDA5 interaction. These findings clearly define molecular determinants for MDA5 inhibition by the paramyxovirus V proteins.

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