Escape from Transcriptional Shutoff during Poliovirus Infection: NF-κB-Responsive Genes IκBa and A20

Doukas, Tammy; Sarnow, Peter

doi:10.1128/jvi.00575-11

Cited by 14 publications

(10 citation statements)

References 46 publications

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“…The importance of all the multipath genes mentioned above relays in their participation together with nfkb2 to target ~ 200 additional genes important for a wide variety of host responses to infection [41]. Consequently with this key position, nfkb have been described as a viral target for shutoff in mammalian viral infections such as herpes [42], poliovirus [43] and rhabdovirus [44]. Shutoff of nfkb has been also reported in salmonid birnavirus infections [45] and in zebrafish after activation of tlr4 [46].…”

Section: Resultsmentioning

confidence: 99%

Identification of Multipath Genes Differentially Expressed in Pathway-Targeted Microarrays in Zebrafish Infected and Surviving Spring Viremia Carp Virus (SVCV) Suggest Preventive Drug Candidates

et al. 2013

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Spring viremia carp virus (SVCV) is a rhabdovirus seasonally affecting warm-water cyprinid fish farming causing high impacts in worldwide economy. Because of the lack of effective preventive treatments, the identification of multipath genes involved in SVCV infection might be an alternative to explore the possibilities of using drugs for seasonal prevention of this fish disease. Because the zebrafish (Danio rerio) is a cyprinid susceptible to SVCV and their genetics and genome sequence are well advanced, it has been chosen as a model for SVCV infections. We have used newly designed pathway-targeted microarrays 3-4-fold enriched for immune/infection functional-relevant probes by using zebrafish orthologous to human genes from selected pathways of the Kyoto Encyclopedia of Genes and Genomes (KEGG). The comparative analysis of differential expression of genes through 20 pathways in 2-day exposed or 30-day survivors of SVCV infection allowed the identification of 16 multipath genes common to more than 6 pathways. In addition, receptors (Toll-like, B-cell, T-cell, RIG1-like) as well as viral RNA infection pathways were identified as the most important human-like pathways targeted by SVCV infection. Furthermore, by using bioinformatic tools to compare the promoter sequences corresponding to up and downregulated multipath gene groups, we identified putative common transcription factors which might be controlling such responses in a coordinated manner. Possible drug candidates to be tested in fish, can be identified now through search of data bases among those associated with the human orthologous to the zebrafish multipath genes. With the use of pathway-targeted microarrays, we identified some of the most important genes and transcription factors which might be implicated in viral shutoff and/or host survival responses after SVCV infection. These results could contribute to develop novel drug-based prevention methods and consolidate the zebrafish/SVCV as a model for vertebrate viral diseases.

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Section: Resultsmentioning

confidence: 99%

Identification of Multipath Genes Differentially Expressed in Pathway-Targeted Microarrays in Zebrafish Infected and Surviving Spring Viremia Carp Virus (SVCV) Suggest Preventive Drug Candidates

et al. 2013

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“…To assess whether host transcription is affected, we monitored transcription of endogenous genes in wild-type-and CrPV-3(R146A)-infected S2 cells. Specifically, we used a 4-thiouridine (4sU) approach whereby 4sU pulse labeling of newly synthesized RNAs can be captured through biotinylation of the thio group followed by purification using streptavidin bead pulldown (66,67). Purified 4sU-labeled mRNAs were monitored by real-time reverse transcription-PCR (RT-PCR) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein

Khong

Kerr

Yeung

et al. 2017

J Virol

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Stress granules (SGs) are cytosolic ribonucleoprotein aggregates that are induced during cellular stress. Several viruses modulate SG formation, suggesting that SGs have an impact on virus infection. However, the mechanisms and impact of modulating SG assembly in infected cells are not completely understood. In this study, we identify the dicistrovirus cricket paralysis virus 1A (CrPV-1A) protein that functions to inhibit SG assembly during infection. Moreover, besides inhibiting RNA interference, CrPV-1A also inhibits host transcription, which indirectly modulates SG assembly. Thus, CrPV-1A is a multifunctional protein. We identify a key R146A residue that is responsible for these effects, and mutant CrPV(R146A) virus infection is attenuated in Drosophila melanogaster S2 cells and adult fruit flies and results in increased SG formation. Treatment of CrPV(R146A)-infected cells with actinomycin D, which represses transcription, restores SG assembly suppression and viral yield. In summary, CrPV-1A modulates several cellular processes to generate a cellular environment that promotes viral translation and replication.IMPORTANCE RNA viruses encode a limited set of viral proteins to modulate an array of cellular processes in order to facilitate viral replication and inhibit antiviral defenses. In this study, we identified a viral protein, called CrPV-1A, within the dicistrovirus cricket paralysis virus that can inhibit host transcription, modulate viral translation, and block a cellular process called stress granule assembly. We also identified a specific amino acid within CrPV-1A that is important for these cellular processes and that mutant viruses containing mutations of CrPV-1A attenuate virus infection. We also demonstrate that the CrPV-1A protein can also modulate cellular processes in human cells, suggesting that the mode of action of CrPV-1A is conserved. We propose that CrPV-1A is a multifunctional, versatile protein that creates a cellular environment in virus-infected cells that permits productive virus infection.

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“…Furthermore, poliovirus 3C inhibits transcription by cleaving TBP and CREB (24,27). On the other hand, host genes can escape poliovirus-induced transcriptional inhibition (40). In this study, we noted that when ectopically expressed in mammalian cells, EV71 3C mediated cleavage of TAB2, TAK1, TAB1, and TAB3, inhibiting NF-B promoter activation.…”

Section: Discussionmentioning

confidence: 68%

Enterovirus 71 3C Inhibits Cytokine Expression through Cleavage of the TAK1/TAB1/TAB2/TAB3 Complex

Lei

Han

Xiao

et al. 2014

J Virol

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Enterovirus 71 (EV71) causes hand, foot, and mouth disease in young children and infants. Severe infection with EV71 can lead to various neurological complications or fatal diseases. However, the mechanism of EV71 pathogenesis is poorly understood. Emerging evidence suggests that EV71 modulates type I interferon (IFN) and cytokine responses. Here, we show that EV71 disables components of the TAB2 complex through the 3C protein. When expressed in mammalian cells, EV71 3C interacts with TAB2 and TAK1, which inhibits NF-B activation. Furthermore, 3C mediates cleavage of TAB2 and its partners, which requires the protease activity. H40D or C147S substitution in the 3C active sites abolishes its activity, whereas R84Q or V154S substitution in the RNA binding domain has no effect. The 3C protein targets TAB2 at Q113-S114, TAK1 at Q360-S361, TAB1 both at Q414-G415 and Q451-S452, and TAB3 at Q173-G174 and Q343-G344. Importantly, overexpression of TAB2 inhibits EV71 replication, whereas addition of cleaved fragments has no effect. Thus, an equilibrium between the TAB2 complex and EV71 3C represents a control point of viral infection. These results suggest that TAK1/TAB1/TAB2/TAB3 cleavage mediated by EV71 may be a mechanism to interfere with inflammatory responses. IMPORTANCEThe TAK1 complex plays a critical role in the activation of NF-B and cytokine production. However, little is known about its connection to enterovirus 71 (EV71). We demonstrate that EV71 3C suppresses cytokine expression via cleavage of the TAK1 complex proteins. EV71 3C interacts with TAB2 and TAK1. Furthermore, overexpression of TAB2 inhibits EV71 replication, whereas addition of cleaved fragment has no effect. These results suggest that the interplay of EV71 and the TAK1 complex influences the outcome of viral infection. E nterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease (HFMD) in young children and infants. Severe infection with EV71 can lead to various neurological complications or even fatal diseases (1). To date, there is no effective treatment for EV71 infection. EV71 is a member of the Picornaviridae family with a single, positive-stranded RNA genome which encodes a single polyprotein precursor. This precursor is proteolytically cleaved to four structural and seven nonstructural proteins during virus infection (1). The nonstructural protein 3C is essential for the precursor cleavage and viral replication (2-4). It also possesses RNA-binding activity (3). Recent reports show that EV71 3C inhibits type I interferon (IFN) responses by targeting innate immune factors, such as RIG-I, TRIF, interferon regulatory factor 7 (IRF7), and IRF9 (5-8).Transforming growth factor-␤-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, which is activated by various stimuli, including Toll-like receptor (TLR) ligands, tumor necrosis factor alpha (TNF-␣), and interleukin-1␤ (IL-1␤) (9, 10). In mammalian cells, TAK1 constitutively binds to the TAK1 binding protein 1 (TAB1), w...

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Escape from Transcriptional Shutoff during Poliovirus Infection: NF-κB-Responsive Genes IκBa and A20

Cited by 14 publications

References 46 publications

Identification of Multipath Genes Differentially Expressed in Pathway-Targeted Microarrays in Zebrafish Infected and Surviving Spring Viremia Carp Virus (SVCV) Suggest Preventive Drug Candidates

Identification of Multipath Genes Differentially Expressed in Pathway-Targeted Microarrays in Zebrafish Infected and Surviving Spring Viremia Carp Virus (SVCV) Suggest Preventive Drug Candidates

Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein

Enterovirus 71 3C Inhibits Cytokine Expression through Cleavage of the TAK1/TAB1/TAB2/TAB3 Complex

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