Endoribonuclease activities of porcine reproductive and respiratory syndrome virus nsp11 was essential for nsp11 to inhibit IFN-β induction

Shi, Xibao; Wang, Li; Li, Xuewu; Zhang, Gaiping; Guo, Junqing; Zhao, Dong; Chai, Shujun; Deng, Ruiguang

doi:10.1016/j.molimm.2011.03.004

Cited by 71 publications

(64 citation statements)

References 40 publications

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“…2C), suggesting that each MCV protein inhibited an event upstream of IRF3 activation. Nsp11 overexpression also did not inhibit constitutively active IRF3, which was expected given that nsp11 is thought to act as an endoribonuclease to target the degradation of MAVS transcripts (49,50). Viral protein level expression was verified by immunoblotting to ensure that the lack of inhibition was not due to a lack of protein expression.…”

Section: Resultsmentioning

confidence: 96%

“…However, the overexpression of MC159, or any other FLIP, did not induce IFN-β enhancer activity in both cell types tested here. The porcine reproductive and respiratory syndrome virus (PRRSV) nsp11 protein is a known inhibitor of IFN-β activation via its ability to inhibit IRF3 and NF-κB (49,50). As would be expected, luciferase activity was low in nsp11-expressing cells and was used as a positive control.…”

Section: Resultsmentioning

confidence: 96%

“…TBK1 protein levels were diminished in cells coexpressing nsp11. Nsp11 possesses endoribonuclease activity and is known to target MAVS (49,50). While nsp11 has not been reported to degrade TBK1 mRNA, it would be reasonable to predict that nsp11 could target other cellular mRNAs.…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of interferon gene activation by death-effector domain-containing proteins from the molluscum contagiosum virus

Randall

Biswas

Selen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Apoptosis, NF-κB activation, and IRF3 activation are a triad of intrinsic immune responses that play crucial roles in the pathogenesis of infectious diseases, cancer, and autoimmunity. FLIPs are a family of viral and cellular proteins initially found to inhibit apoptosis and more recently to either up-or down-regulate NF-κB. As such, a broad role for FLIPs in disease regulation is postulated, but exactly how a FLIP performs such multifunctional roles remains to be established. Here we examine FLIPs (MC159 and MC160) encoded by the molluscum contagiosum virus, a dermatotropic poxvirus causing skin infections common in children and immunocompromised individuals, to better understand their roles in viral pathogenesis. While studying their molecular mechanisms responsible for NF-κB inhibition, we discovered that each protein inhibited IRF3-controlled luciferase activity, identifying a unique function for FLIPs. MC159 and MC160 each inhibited TBK1 phosphorylation, confirming this unique function. Surprisingly, MC159 coimmunoprecipitated with TBK1 and IKKe but MC160 did not, suggesting that these homologs use distinct molecular mechanisms to inhibit IRF3 activation. Equally surprising was the finding that the FLIP regions necessary for TBK1 inhibition were distinct from those MC159 or MC160 regions previously defined to inhibit NF-κB or apoptosis. These data reveal previously unappreciated complexities of FLIPs, and that subtle differences within the conserved regions of FLIPs possess distinct molecular and structural fingerprints that define crucial differences in biological activities. A future comparison of mechanistic differences between viral FLIP proteins can provide new means of precisely manipulating distinct aspects of intrinsic immune responses.host-pathogen interactions | immune evasion I FN-β provides an important defense against viral infections (1, 2). The pathway leading to IFN-β production is well characterized. By-products of viral infection, such as dsRNA, are detected by upstream cellular sensors, including retinoic acidinducible gene 1 (RIG-I), melanoma differentiation-associated factor gene 5 (MDA5), and STING. RIG-I and MDA5 proteins then interact with mitochondrial antiviral signaling (MAVS) adaptor protein to trigger MAVS activation (3-8). The TNF receptor-associated factor 3 (TRAF3) adaptor protein is recruited to this complex, resulting in the activation of the kinase complex TANK-binding kinase 1 (TBK1)-IκB kinase e (IKKe) (9-11). Alternatively, the STING molecule activates TBK1-IKKe (12, 13). In either case, TBK1-IKKe phosphorylates and activates IFN regulatory factor (IRF) transcription factor proteins (11), which migrate to the nucleus to bind to the IFN-β enhancer. IFN-β is secreted and binds to the IFN receptor (IFNR). This initiates a second signaling cascade in infected and neighboring cells, which promotes expression of IFN-α and IFN-stimulated genes whose products contribute to an antiviral state.Identification of the above members of the IFN-β signal transduction pathway also resul...

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 96%

See 1 more Smart Citation

Inhibition of interferon gene activation by death-effector domain-containing proteins from the molluscum contagiosum virus

Randall

Biswas

Selen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…However, despite recent advances in our understanding of PRRSV replicase polyproteins (Li et al, 2014;Liu et al, 2012;Shi et al, 2011;Sun et al, 2012), various aspects of nsps remain unclear. PRRSV nsp7 is the largest subunit in the nsp5-nsp8 region, and is flanked by nsp6 and nsp8.…”

Section: Discussionmentioning

confidence: 99%

“…ORF1a and ORF1b occupy approximately 75% of the viral genome and encode the replicase polyproteins pp1a and pp1ab, respectively, which are cleaved into at least 14 functional nsps by viral protease (den Boon et al, 1995;Fang and Snijder, 2010;Snijder et al, 1994). Recent studies have revealed that PRRSV nsp2 is involved modulating type 1 interferon (IFN) activity (Sun et al, 2012), nsp9 and nsp10 contribute to the fatal virulence of highly-pathogenic PRRSV (Li et al, 2014) plays an important role in IFN inhibition and viral genome synthesis (Shi et al, 2011). Nsp1, nsp2, and nsp7 were shown to induce high levels of antibody responses during PRRSV infection (Brown et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Characterization and utility of phages bearing peptides with affinity to porcine reproductive and respiratory syndrome virus nsp7 protein

Wang¹,

Liu²,

Cui³

et al. 2015

Journal of Virological Methods

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Transcriptional profiles of PBMCs from pigs infected with three genetically diverse porcine reproductive and respiratory syndrome virus strains

et al. 2018

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Porcine reproductive and respiratory syndrome virus is the cause of reproductive failure in sows and respiratory disease in young pigs, which has been considered as one of the most costly diseases to the worldwide pig industry for almost 30 years. This study used microarray-based transcriptomic analysis of PBMCs from experimentally infected pigs to explore the patterns of immune dysregulation after infection with two East European PRRSV strains from subtype 2 (BOR and ILI) in comparison to a Danish subtype 1 strain (DAN). Transcriptional profiles were determined at day 7 post infection in three tested groups of pigs and analysed in comparison with the expression profile of control group. Microarray analysis revealed differential regulation (> 1.5-fold change) of 4253 and 7335 genes in groups infected with BOR and ILI strains, respectively, and of 12518 genes in pigs infected with Danish strain. Subtype 2 PRRSV strains showed greater induction of many genes, especially those involved in innate immunity, such as interferon stimulated antiviral genes and inflammatory markers. Functional analysis of the microarray data revealed a significant up-regulation of genes involved in processes such as acute phase response, granulocyte and agranulocyte adhesion and diapedesis, as well as down-regulation of genes enrolled in pathways engaged in protein synthesis, cell division, as well as B and T cell signaling. This study provided an insight into the host response to three different PRRSV strains at a molecular level and demonstrated variability between strains of different pathogenicity level.Electronic supplementary materialThe online version of this article (10.1007/s11033-018-4204-x) contains supplementary material, which is available to authorized users.

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Endoribonuclease activities of porcine reproductive and respiratory syndrome virus nsp11 was essential for nsp11 to inhibit IFN-β induction

Cited by 71 publications

References 40 publications

Inhibition of interferon gene activation by death-effector domain-containing proteins from the molluscum contagiosum virus

Inhibition of interferon gene activation by death-effector domain-containing proteins from the molluscum contagiosum virus

Characterization and utility of phages bearing peptides with affinity to porcine reproductive and respiratory syndrome virus nsp7 protein

Transcriptional profiles of PBMCs from pigs infected with three genetically diverse porcine reproductive and respiratory syndrome virus strains

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