C Proteins: Controllers of Orderly Paramyxovirus Replication and of the Innate Immune Response

Siering, Oliver; Cattaneo, Roberto; Pfaller, Christian K.

doi:10.3390/v14010137

Cited by 13 publications

(7 citation statements)

References 205 publications

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“…Notably, ADAR1p150 expression was not detected after either EV-D68 or HPIV3 infection. In line with this notion, ADAR1p150 is mainly induced by IFN, while EV-D68 2A and 3C proteases can inhibit the production of type I IFN[ 31 , 32 ], and the C protein of the Paramyxoviridae family generally bind and interfere with several cytoplasmic proteins which are required for IFN induction [ 33 ]. Therefore, we speculate that interruption of the generation of IFN, triggered by EV-D68 and HPIV3 viral proteins, was responsible for the undetected ADARp150.…”

Section: Discussionmentioning

confidence: 99%

ADAR1p110 promotes Enterovirus D68 replication through its deaminase domain and inhibition of PKR pathway

Zhang

Wang

Chen

et al. 2022

Virol J

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Background Severe respiratory and neurological diseases caused by human enterovirus D68 (EV-D68) pose a serious threat to public health, and there are currently no effective drugs and vaccines. Adenosine deaminase acting on RNA1 (ADAR1) has diverse biological functions in various viral infections, but its role in EV-D68 infections remains undetermined. Methods Rhabdomyosarcoma (RD) and human embryonic kidney 293 T (293 T) cells, and HeLa cells were used to evaluate the expression level of ADAR1 upon EV-D68 (Fermon strain) and human parainfluenza virus type 3 (HPIV3; NIH47885) infection, respectively. Knockdown through silencing RNA (siRNA) and overexpression of either ADAR1p110 or ADAR1p150 in cells were used to determine the function of the two proteins after viral infection. ADAR1p110 double-stranded RNA binding domains (dsRBDs) deletion mutation was generated using a seamless clone kit. The expression of ADAR1, EV-D68 VP1, and HPIV3 hemagglutinin–neuraminidase (HN) proteins was identified using western blotting. The median tissue culture infectious dose (TCID50) was applied to detect viral titers. The transcription level of EV-D68 mRNA was analyzed using reverse transcription-quantitative PCR (RT-qPCR) and the viral 5′-untranslated region (5′-UTR)-mediated translation was analyzed using a dual luciferase reporter system. Conclusion We found that the transcription and expression of ADAR1 was inhibited upon EV-D68 infection. RNA interference of endogenous ADAR1 decreased VP1 protein expression and viral titers, while overexpression of ADAR1p110, but not ADAR1p150, facilitated viral replication. Immunofluorescence assays showed that ADAR1p110 migrated from the nucleus to the cytoplasm after EV-D68 infection. Further, ADAR1p110 lost its pro-viral ability after mutations of the active sites in the deaminase domain, and 5′-UTR sequencing of the viral genome revealed that ADAR1p110 likely plays a role in EV-D68 RNA editing. In addition, after ADAR1 knockdown, the levels of both phosphorylated double-stranded RNA dependent protein kinase (p-PKR) and phosphorylated eukaryotic initiation factor 2α (p-eIF2α) increased. Attenuated translation activity of the viral genome 5′-UTR was also observed in the dual-luciferase reporter assay. Lastly, the deletion of ADAR1p110 dsRBDs increased the level of p-PKR, which correlated with a decreased VP1 expression, indicating that the promotion of EV-D68 replication by ADAR1p110 is also related to the inhibition of PKR activation by its dsRBDs. Our study illustrates that ADAR1p110 is a novel pro-viral factor of EV-D68 replication and provides a theoretical basis for EV-D68 antiviral research.

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Section: Discussionmentioning

confidence: 99%

ADAR1p110 promotes Enterovirus D68 replication through its deaminase domain and inhibition of PKR pathway

Zhang

Wang

Chen

et al. 2022

Virol J

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“…The results of studies conducted in vitro with viruses deficient of C proteins are consistent with in vivo studies using animal models or natural hosts. The Morbillivirus , Henipavirus , and Respirovirus lacking C protein expression showed a low pathogenesis in vivo, confirming their role as virulence factors [ 114 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 ].…”

Section: Role Of the P V And W Proteins In Ifn Antagonismmentioning

confidence: 95%

“…From the analyzed data, it is clear that C proteins, despite not being present in all the paramyxovirus genera (they are produced in approximately one third (26 on 63) of the genome sequence of paramyxovirus species sequenced so far [ 194 ]), possess an important role in antagonizing both IFN induction and signaling pathways. The results of studies conducted in vitro with viruses deficient of C proteins are consistent with in vivo studies using animal models or natural hosts.…”

Section: Role Of the P V And W Proteins In Ifn Antagonismmentioning

confidence: 99%

Type I and Type II Interferon Antagonism Strategies Used by Paramyxoviridae: Previous and New Discoveries, in Comparison

Pisanelli

Pagnini

Iovane

et al. 2022

Viruses

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Paramyxoviridae is a viral family within the order of Mononegavirales; they are negative single-strand RNA viruses that can cause significant diseases in both humans and animals. In order to replicate, paramyxoviruses–as any other viruses–have to bypass an important protective mechanism developed by the host’s cells: the defensive line driven by interferon. Once the viruses are recognized, the cells start the production of type I and type III interferons, which leads to the activation of hundreds of genes, many of which encode proteins with the specific function to reduce viral replication. Type II interferon is produced by active immune cells through a different signaling pathway, and activates a diverse range of genes with the same objective to block viral replication. As a result of this selective pressure, viruses have evolved different strategies to avoid the defensive function of interferons. The strategies employed by the different viral species to fight the interferon system include a number of sophisticated mechanisms. Here we analyzed the current status of the various strategies used by paramyxoviruses to subvert type I, II, and III interferon responses.

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“…As mentioned above, the V protein of CPIV inhibits host innate immune responses through multiple pathways; however, consistent with the paramyxovirus described above, CPIV generates snapback DVGs during replication and induces host innate immune responses during replication ( Wignall-Fleming et al, 2020 ). However, similar to the C protein, the V protein is a product of RNA editing of the P gene ( Siering et al, 2022 ). Whether the V protein inhibits the production of viral DVGs is unclear, and this possibility and the intrinsic mechanism need to be further studied.…”

Section: Research Progress Into the Interaction Between The V Protein...mentioning

confidence: 99%

Molecular biology of canine parainfluenza virus V protein and its potential applications in tumor immunotherapy

Cheng,

Zhang,

Cai

et al. 2023

Front. Microbiol.

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Canine parainfluenza virus (CPIV) is a zoonotic virus that is widely distributed and is the main pathogen causing canine infectious respiratory disease (CIRD), also known as “kennel cough,” in dogs. The CPIV-V protein is the only nonstructural protein of the virus and plays an important role in multiple stages of the virus life cycle by inhibiting apoptosis, altering the host cell cycle and interfering with the interferon response. In addition, studies have shown that the V protein has potential applications in the field of immunotherapy in oncolytic virus therapy or self-amplifying RNA vaccines. In this review, the biosynthesis, structural characteristics and functions of the CPIV-V protein are reviewed with an emphasis on how it facilitates viral immune escape and its potential applications in the field of immunotherapy. Therefore, this review provides a scientific basis for research into the CPIV-V protein and its potential applications.

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C Proteins: Controllers of Orderly Paramyxovirus Replication and of the Innate Immune Response

Cited by 13 publications

References 205 publications

ADAR1p110 promotes Enterovirus D68 replication through its deaminase domain and inhibition of PKR pathway

ADAR1p110 promotes Enterovirus D68 replication through its deaminase domain and inhibition of PKR pathway

Type I and Type II Interferon Antagonism Strategies Used by Paramyxoviridae: Previous and New Discoveries, in Comparison

Molecular biology of canine parainfluenza virus V protein and its potential applications in tumor immunotherapy

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