Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription

Fu, Yu-Zhi; Su, Shan; Zou, Hong-Mei; Guo, Yi; Wang, Suyun; Li, Shu; Luo, Min‐Hua; Wang, Yan-Yi

doi:10.1128/jvi.00181-19

Cited by 29 publications

(25 citation statements)

References 62 publications

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“…During coevolution with hosts, viruses have evolved multiple mechanisms to evade host immune defense. [32][33][34] How SARS-CoV-2 evades the host immune defense is not well understood. In this study, we identified the SARS-CoV-2 M protein as a factor underlying the inhibition of host antiviral innate immunity by directly targeting the central adaptor MAVS in the RLR-mediated induction of type I IFNs.…”

Section: Discussionmentioning

confidence: 99%

“…Coimmunoprecipitation and immunoblot analysis Coimmunoprecipitation and immunoblot analyses were performed as previously described. 34,44 In brief, for coimmunoprecipitation, cells (1 × 10 7 ) were lysed in 1 mL of NP-40 lysis buffer (20 mM Tris-HCl [pH 7.4], 150 mM NaCl, 1 mM EDTA, 1% Nonidet P-40, 10 μg/mL aprotinin, 10 μg/mL leupeptin, and 1 mM phenylmethylsulfonyl fluoride). For direct analysis of protein expression, cells were lysed with SDS-PAGE loading buffer and then ultrasonicated.…”

Section: Plasmid Constructionmentioning

confidence: 99%

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SARS-CoV-2 membrane glycoprotein M antagonizes the MAVS-mediated innate antiviral response

et al. 2020

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A novel SARS-related coronavirus (SARS-CoV-2) has recently emerged as a serious pathogen that causes high morbidity and substantial mortality. However, the mechanisms by which SARS-CoV-2 evades host immunity remain poorly understood. Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions.

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Section: Discussionmentioning

confidence: 99%

Section: Plasmid Constructionmentioning

confidence: 99%

SARS-CoV-2 membrane glycoprotein M antagonizes the MAVS-mediated innate antiviral response

et al. 2020

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“…(iii) KSHV latency-associated nuclear antigen 1 (LANA-1) competes with IRF3 for binding to the PRDIII-I region and in this way interferes with stable association of IRF3 to the target DNA [ 235 ]. The DNA polymerase subunit UL44 of HCMV was recently reported to act in a similar way [ 236 ]: Upon HCMV infection, exogenously expressed UL44 could be demonstrated to associate with the IFNβ promoter region in a chromatin immunoprecipitation assay and in parallel UL44 interfered with binding of the central transcription factors IRF3 and p65. Additionally, UL44 interacts with both transcription factors irrespective of their phosphorylation status.…”

Section: Saboteurs Of the Main Act—viral Modulation Of Activated Imentioning

confidence: 99%

Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression

Schwanke

Stempel

Brinkmann

2020

Viruses

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The type I interferon (IFN) response is a principal component of our immune system that allows to counter a viral attack immediately upon viral entry into host cells. Upon engagement of aberrantly localised nucleic acids, germline-encoded pattern recognition receptors convey their find via a signalling cascade to prompt kinase-mediated activation of a specific set of five transcription factors. Within the nucleus, the coordinated interaction of these dimeric transcription factors with coactivators and the basal RNA transcription machinery is required to access the gene encoding the type I IFN IFNβ (IFNB1). Virus-induced release of IFNβ then induces the antiviral state of the system and mediates further mechanisms for defence. Due to its key role during the induction of the initial IFN response, the activity of the transcription factor interferon regulatory factor 3 (IRF3) is tightly regulated by the host and fiercely targeted by viral proteins at all conceivable levels. In this review, we will revisit the steps enabling the trans-activating potential of IRF3 after its activation and the subsequent assembly of the multi-protein complex at the IFNβ enhancer that controls gene expression. Further, we will inspect the regulatory mechanisms of these steps imposed by the host cell and present the manifold strategies viruses have evolved to intervene with IFNβ transcription downstream of IRF3 activation in order to secure establishment of a productive infection.

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“…Many other viral infections have been shown to correlate with the functionality of β-catenin. For example, both Porcine Circovirus-like virus and Human Cytomegalovirus inhibit the classical Wnt signal pathway post-infection [8,31]. When Wnt/β-catenin pathway is at the deactivation stage, the protein kinase GSK3β phosphorylates serine at site 33 and 37 on β-catenin [17].…”

Section: Discussionmentioning

confidence: 99%

Beta-catenin inhibits bovine parainfluenza virus type 3 replication via innate immunity pathway

et al. 2020

BMC Vet Res

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Background: Bovine parainfluenza virus type 3 (BPIV3) is one of the important viral respiratory agents associated with the bovine respiratory disease complex (BRDC) in cattle. Previous study has demonstrated that infection of BPIV3 causes innate immune response within the host cell. β-catenin is a key component of the Wnt/β-catenin signal pathway which is involved in the regulation of interferon-beta (IFN-β) transcription. Some viruses can activate while others can inhibit the Wnt/β-catenin signaling pathway. However, the role of β-catenin in BPIV3 infection remains unclear.Results: Here we found that the expression of β-catenin mRNA was up-regulated and β-catenin protein was downregulated after BPIV3 infection in MDBK cells. Moreover, it was confirmed that overexpression of β-catenin suppressed BPIV3 replication and knockdown of β-catenin promoted viral replication, suggesting that β-catenin inhibits BPIV3 replication. Furthermore, IFN-β signal pathway and virus titer analysis using the GSK3β inhibitor (LiCl) revealed that Wnt/β-catenin can serve as a mechanism to suppress virus replication in infected cells. The results indicated that LiCl promoted the expression and accumulation in the nucleus of β-catenin, which further promoted the expression of IFN-β and OSA1 and suppressed BPIV3 replication. Most importantly, BPIV3 down-regulating βcatenin protein expression was due to degradation of GSK3β mediated proteasome pathway. Conclusions: In summary, we discovered the relationship between β-catenin and BPIV3 replication. These results provided further insight into the study of BPIV3 pathogenesis.

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Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription

Cited by 29 publications

References 62 publications

SARS-CoV-2 membrane glycoprotein M antagonizes the MAVS-mediated innate antiviral response

SARS-CoV-2 membrane glycoprotein M antagonizes the MAVS-mediated innate antiviral response

Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression

Beta-catenin inhibits bovine parainfluenza virus type 3 replication via innate immunity pathway

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