The Superimposed Deubiquitination Effect of OTULIN and Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Nsp11 Promotes Multiplication of PRRSV

Su, Yu; Shi, Peidian; Zhang, Lilin; Lu, Dong; Zhao, Chen; Li, Ruiqiao; Zhang, Lei; Huang, Jinhai

doi:10.1128/jvi.00175-18

Cited by 30 publications

(28 citation statements)

References 48 publications

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“…(iii) nsp11 removes the ubiquitin chains from IκBα (inhibitor of NF-κB alpha), thereby preventing the proteasomal degradation of IκBα and subsequent liberation of NF-κB ( 39 ). (iv) nsp11 recruits the OTU deubiquitinase with linear linkage specificity (OTULIN) to enhance its ability to remove the cellular protein ubiquitin associated with innate immunity, resulting in the additive effect of suppressing type I IFN production ( 40 ). However, whether nsp11 also regulates IFN signaling remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Porcine Reproductive and Respiratory Syndrome Virus nsp11 Antagonizes Type I Interferon Signaling by Targeting IRF9

Wang

Chen

et al. 2019

J Virol

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Porcine reproductive and respiratory syndrome virus (PRRSV) is an arterivirus from the Nidovirales order that causes reproductive failure and respiratory disease in pigs and poses a constant threat to the global pig industry. The PRRSV-encoded nonstructural protein 11 (nsp11) is a nidovirus-specific endoribonuclease (NendoU) that is conserved throughout the Arteriviridae and Coronaviridae families. Previously, our research and that of others demonstrated that PRRSV nsp11 inhibits type I interferon (IFN) production through NendoU activity-dependent mechanisms. Here, we found that PRRSV nsp11 also inhibited IFN-stimulated response element (ISRE) promoter activity and subsequent transcription of IFN-stimulated genes (ISGs). Detailed analysis showed that nsp11 targeted interferon regulatory factor 9 (IRF9), but not transducer and activator of transcription 1 (STAT1) or STAT2, key molecules in the type I IFN signaling pathway. Furthermore, the nsp11-IRF9 interaction impaired the formation and nuclear translocation of the transcription factor complex IFN-stimulated gene factor 3 (ISGF3) in both nsp11-overexpressed and PRRSV-infected cells. Importantly, nsp11 mutations (H129A, H144A, and K173A) that ablate NendoU activity or its cell cytotoxicity also interacted with IRF9 and retained the ability to block IFN signaling, indicating that the nsp11-IRF9 interaction is independent of NendoU activity or cell cytotoxicity of nsp11. Taking the results together, our study demonstrated that PRRSV nsp11 antagonizes type I IFN signaling by targeting IRF9 via a NendoU activity-independent mechanism, and this report describes a novel strategy evolved by PRRSV to counteract host innate antiviral responses, revealing a potential new function for PRRSV nsp11 in type I IFN signaling. IMPORTANCE The nidovirus-specific endoribonuclease (NendoU) encoded by PRRSV nonstructural protein 11 (nsp11) is a unique NendoU of nidoviruses that infect vertebrates; thus, it is an attractive target for the development of antinidovirus drugs. Previous studies have revealed that the NendoU of nidoviruses, including porcine reproductive and respiratory syndrome virus (PRRSV) and human coronavirus 229E (HCoV-229E), acts as a type I interferon (IFN) antagonist. Here, for the first time, we demonstrated that overexpression of PRRSV nsp11 also inhibits IFN signaling by targeting the C-terminal interferon regulatory factor (IRF) association domain of IRF9. This interaction impaired the ability of IRF9 to form the transcription factor complex IFNstimulated gene factor 3 (ISGF3) and to act as a signaling protein of IFN signaling. Collectively, our data identify IRF9 as a natural target of PRRSV NendoU and reveal a novel mechanism evolved by an arterivirus to counteract innate immune signaling.KEYWORDS interferon regulatory factor 9, nidovirus-specific endoribonuclease, porcine reproductive and respiratory syndrome virus, type I IFN signaling P orcine reproductive and respiratory syndrome (PRRS) is the most economically important infectious disease in the pig indu...

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Section: Discussionmentioning

confidence: 99%

Porcine Reproductive and Respiratory Syndrome Virus nsp11 Antagonizes Type I Interferon Signaling by Targeting IRF9

Wang

Chen

et al. 2019

J Virol

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“…Besides, TRAIP has been reported to be a gene involved in innate immunity (39). Therefore, we further explored whether there is an interaction between the TRAIP and PRRSV non-structural proteins nsp1, nsp4, nsp11, each of which is a major protein involved in inhibiting the IFN-β and NF-κB promoters (41, 43, 44). We first observed that Flag-tagged TRAIP interacted with Myc-nsp1 (Supplementary Figure 1), and the interaction between TRAIP and nsp1 was confirmed by co-immunoprecipitation (Supplementary Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…Human embryonic kidney (HEK) 293T cells and HeLa cells were maintained in Dulbecco's modified Eagle's medium (DMEM, Gibco) with 10% FBS supplemented with an antibiotic-antimycotic mixture of 100 mg/ml streptomycin, 100 IU/ml penicillin and 50 U/ml amphotericin B. The cells were maintained in a humidified 5% CO 2 incubator at 37°C.The PRRSV-JXwn06 strain was used in our study and the titer was determined to be 104 PFU/ml as previously described (41).…”

Section: Methodsmentioning

confidence: 99%

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Dual Regulation of Host TRAIP Post-translation and Nuclear/Plasma Distribution by Porcine Reproductive and Respiratory Syndrome Virus Non-structural Protein 1α Promotes Viral Proliferation

Shi

et al. 2018

Front. Immunol.

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In this study, we show that porcine reproductive and respiratory syndrome virus (PRRSV) non-structural protein 1α (nsp1α) facilitates PRRSV escape from innate immune by modulating nuclear to cytoplasmic translocation and distribution ratio of TRAIP to promote virus proliferation. Mechanistically, TRAIP interacts with PRRSV nsp1α via its K205 site, while NSP1α decreases the SUMOylation and K48 ubiquitination independent of the TRAIP interaction K205 site. Modulation of the dual modification of TRAIP by PRRSV nsp1α results in over-enrichment of TRAIP in the cytoplasm. Enrichment of nsp1α-induced cytoplasmic TRAIP in turn leads to excessive K48 ubiquitination and degradation of serine/threonine-protein kinase (TBK1), thereby antagonizing TBK1-IRF3-IFN signaling. This study proposes a novel mechanism by which PRRSV utilizes host proteins to regulate innate immunity. Findings from this study provides novel perspective to advance our understanding in the pathogenesis of PRRSV.

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“…The procedure for confocal microscopy has been described previously (Su et al, 2018). IPEC-J2 cells were seeded on 12-well plates until the cell density was about 60%˜70%.…”

Section: Immunofluorescencementioning

confidence: 99%

PEDV nsp16 negatively regulates innate immunity to promote viral proliferation

Shi

et al. 2019

Virus Research

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Type-I IFNs (IFN-I) provide a key mediator of innate antiviral response during virus proliferation. Porcine epidemic diarrhea virus (PEDV), which causes diarrhea in swine of all ages, is a worldwide-distributed alphacoronavirus with economic importance. Here, we screened PEDV RNA modification enzymes involved in regulating antiviral response. Whereas the PEDV nsp13 barely regulates type I IFN, inflammatory cytokines (IL-6, TNF-a) and MHCII, nsp16 and nsp14 (to a lesser extent) down-regulate these antiviral effectors. Importantly, we found nsp16 KDKE tetrad appears to play a key role in interferon inhibition by mutating the D129 catalytic residue. Mechanistically, nsp16 down-regulates the activities of RIG-I and MDA5 mediated IFN-β and ISRE. In turn, the mRNA levels of IFIT family members (IFIT1, IFIT2, IFIT3) was inhibited in cells overexpressing nsp16. In addition, nsp10 enhanced the inhibitory effect of nsp16 on IFN-β. Altogether these results indicate PEDV nsp16 negatively regulates innate immunity to promote viral proliferation. Findings from this study provides novel perspective to advance the understanding in the pathogenesis of PEDV.

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The Superimposed Deubiquitination Effect of OTULIN and Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Nsp11 Promotes Multiplication of PRRSV

Cited by 30 publications

References 48 publications

Porcine Reproductive and Respiratory Syndrome Virus nsp11 Antagonizes Type I Interferon Signaling by Targeting IRF9

Porcine Reproductive and Respiratory Syndrome Virus nsp11 Antagonizes Type I Interferon Signaling by Targeting IRF9

Dual Regulation of Host TRAIP Post-translation and Nuclear/Plasma Distribution by Porcine Reproductive and Respiratory Syndrome Virus Non-structural Protein 1α Promotes Viral Proliferation

PEDV nsp16 negatively regulates innate immunity to promote viral proliferation

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