The N-terminal domain of Npro of classical swine fever virus determines its stability and regulates type I IFN production

Mine, Junki; Tamura, Tomokazu; Mitsuhashi, Kei; Okamatsu, Masatoshi; Parchariyanon, Sujira; Pinyochon, Wasana; Ruggli, Nicolas; Tratschin, Jon-Duri; Kida, Hiroshi; Sakoda, Yoshihiro

doi:10.1099/vir.0.000132

Cited by 14 publications

(10 citation statements)

References 33 publications

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“…While MG132 does not directly affect the mRNA levels of ISGs in cells without CSFV (Figure 7), MG132 may regulate the expressions of ISGs through modulating the levels of related immune molecules. Viral proteins N pro , C, and p7 of CSFV have been reported to be degraded by 26S proteasome (Seago et al, 2010;Lin et al, 2014;Mine et al, 2015;Chen et al, 2019), and we have found that several other viral proteins are also affected by 26S proteasome (data not shown). Considering the relationships between CSFV viral proteins, the innate immune system and the 26S proteasome, the way that MG132 inhibits the replication of CSFV may need more detailed investigations.…”

Section: Discussionmentioning

confidence: 57%

MG132 Attenuates the Replication of Classical Swine Fever Virus in vitro

Chen

Fan

et al. 2020

Front. Microbiol.

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The 26S proteasome, in charge of intracellular protein degradation, plays significant roles in the modulation of various cellular activities as well as in the interplay between virus and host. However, studies about the relationship between 26S proteasome and classical swine fever virus (CSFV) is limited up to now. MG132 is a proteasome inhibitor and has been extensively used in studies about replication of many viruses. Herein, we investigated the role of MG132 in CSFV replication and results showed that MG132 significantly decreased virus titers and viral RNA copies in CSFV-infected PK-15 cells. Further studies demonstrated that MG132 upregulated the expression of several interferon-stimulated genes (ISGs), in CSFV-infected cells. Since the activation of ISGs is controlled by the JAK-STAT signal pathway, we next examined the effect of MG132 on the expression and localization of key molecular STAT1 in the infected cells using Western blot and confocal laser scanning microscopy, respectively. Results showed that CSFV infection and viral NS4A protein decreased the protein level of STAT1, and MG132 promoted the accumulation of STAT1 in the nucleus of cells adjacent to the CSFVinfected cells. Besides, MG132 did not affect the expressions of IFN-α, STAT1, Mx1, OAS1, and PKR genes in cells without CSFV. In conclusion, we identify that MG132 significantly inhibits CSFV replication in vitro, in which the activation of the JAK-STAT pathway and the subsequent upregulation of expressions of ISGs might play significant roles, providing a potential preventive method for CSF.

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Section: Discussionmentioning

confidence: 57%

MG132 Attenuates the Replication of Classical Swine Fever Virus in vitro

Chen

Fan

et al. 2020

Front. Microbiol.

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“…In a previous report, the replacement of the C-terminal of the core protein and the full-length of E rns of a CSFV vaccine strain resulted in the conversion of the END phenotype without the abrogation of its RNase activity [ 5 ]. Combined with this, this study might propose alternative critical residues for regulating the type I interferon induction, as in the case of N pro [ 34 ]. However, synergetic effects with other amino acid substitutions should be considered to clarify the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 95%

Characteristics of Classical Swine Fever Virus Variants Derived from Live Attenuated GPE− Vaccine Seed

Kim

Loc

Hirose

et al. 2021

Viruses

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The GPE− strain is a live attenuated vaccine for classical swine fever (CSF) developed in Japan. In the context of increasing attention for the differentiating infected from vaccinated animals (DIVA) concept, the achievement of CSF eradication with the GPE− proposes it as a preferable backbone for a recombinant CSF marker vaccine. While its infectious cDNA clone, vGPE−, is well characterized, 10 amino acid substitutions were recognized in the genome, compared to the original GPE− vaccine seed. To clarify the GPE− seed availability, this study aimed to generate and characterize a clone possessing the identical amino acid sequence to the GPE− seed. The attempt resulted in the loss of the infectious GPE− seed clone production due to the impaired replication by an amino acid substitution in the viral polymerase NS5B. Accordingly, replication-competent GPE− seed variant clones were produced. Although they were mostly restricted to propagate in the tonsils of pigs, similarly to vGPE−, their type I interferon-inducing capacity was significantly lower than that of vGPE−. Taken together, vGPE− mainly retains ideal properties for the CSF vaccine, compared with the seed variants, and is probably useful in the development of a CSF marker vaccine.

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“…The N pro s of CSFV and BVDV directly bind IRF3 and induce degradation of the factor by the host proteasome, thus interfering with IFN production . According to point mutation experiments, both the protease domain and the zinc‐binding domain are essential for N pro binding to IRF3 .…”

Section: Rna‐virus Proteases Interfering With the Host Innate Immune mentioning

confidence: 99%

RNA‐virus proteases counteracting host innate immunity

Lei

Hilgenfeld

2017

FEBS Letters

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Virus invasion triggers host immune responses, in particular, innate immune responses. Pathogen‐associated molecular patterns of viruses (such as dsRNA, ssRNA, or viral proteins) released during virus replication are detected by the corresponding pattern‐recognition receptors of the host, and innate immune responses are induced. Through production of type‐I and type‐III interferons as well as various other cytokines, the host innate immune system forms the frontline to protect host cells and inhibit virus infection. Not surprisingly, viruses have evolved diverse strategies to counter this antiviral system. In this review, we discuss the multiple strategies used by proteases of positive‐sense single‐stranded RNA viruses of the families Picornaviridae, Coronaviridae, and Flaviviridae, when counteracting host innate immune responses.

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The N-terminal domain of Npro of classical swine fever virus determines its stability and regulates type I IFN production

Abstract: The viral protein N pro is unique to the genus Pestivirus within the family Flaviviridae. After

Cited by 14 publications

References 33 publications

MG132 Attenuates the Replication of Classical Swine Fever Virus in vitro

MG132 Attenuates the Replication of Classical Swine Fever Virus in vitro

Characteristics of Classical Swine Fever Virus Variants Derived from Live Attenuated GPE− Vaccine Seed

RNA‐virus proteases counteracting host innate immunity

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