The small nuclear ribonucleoprotein U1A interacts with NS5 from yellow fever virus

Bronzoni, Roberta Vieira de Morais; Madrid, Maria Carolina Ferrari Sarkis; Duarte, Danilo V.B.; Pellegrini, Vanessa O. A.; Pacca, Carolina Colombelli; Carmo, Ana Carolina Viegas; Zanelli, Cleslei Fernando; Valentini, Sandro Roberto; Santacruz-Pérez, Carolina; Barbosa, J.A.R.G.; Lutz, Carol S.; Rahal, Paula; Nogueira, Maurício Lacerda

doi:10.1007/s00705-011-0927-x

Cited by 7 publications

(8 citation statements)

References 38 publications

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“…As reported previously [30], the production of a homology model for the RNA polymerase domain of the YFV NS5 protein showed that this region of interaction (ID) is exposed and potentially capable of forming interactions. We also demonstrated that ID from the dengue 4, dengue 3, and Saint Louis encephalitis viruses interact with eIF3L, suggesting that this interaction is important for other members of the genus.…”

Section: Discussionmentioning

confidence: 69%

“…We also demonstrated that ID from the dengue 4, dengue 3, and Saint Louis encephalitis viruses interact with eIF3L, suggesting that this interaction is important for other members of the genus. Accordingly, when the YFV sequence was compared to the sequences of other flaviviruses, a region of homology from residues 20 to 80 was identified [30]. Mutations in the FWELV motif of ID abolished the interaction with eIF3L, suggesting that the amino acids FWELV are critical for the ID interaction with eIF3L.…”

Section: Discussionmentioning

confidence: 99%

“…The three mutations produced in this region may have led to changes in protein conformation, preventing possible interactions with other cellular proteins. However, the data from another study in our laboratory [30] have demonstrated that the same mutations do not affect the interaction of the ID domain with the cellular small ribonucleoprotein polypeptide A (U1A), indicating that the structure of the domain is not significantly altered and is potentially capable of interacting with other molecules.…”

Section: Discussionmentioning

confidence: 99%

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The eukaryotic translation initiation factor 3 subunit L protein interacts with FlavivirusNS5 and may modulate yellow fever virus replication

Morais

Terzian

Duarte

et al. 2013

Virol J

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BackgroundYellow fever virus (YFV) belongs to the Flavivirus genus and causes an important disease. An alarming resurgence of viral circulation and the expansion of YFV-endemic zones have been detected in Africa and South America in recent years. NS5 is a viral protein that contains methyltransferase and RNA-dependent RNA polymerase (RdRp) domains, which are essential for viral replication, and the interactions between NS5 and cellular proteins have been studied to better understand viral replication. The aim of this study was to characterize the interaction of the NS5 protein with eukaryotic translation initiation factor 3 subunit L (eIF3L) and to evaluate the role of eIF3L in yellow fever replication.MethodsTo identify interactions of YFV NS5 with cellular proteins, we performed a two-hybrid screen using the YFV NS5 RdRp domain as bait with a human cDNA library, and RNApol deletion mutants were generated and analyzed using the two-hybrid system for mapping the interactions. The RNApol region involved was segmented into three fragments and analyzed using an eIF3L-expressing yeast strain. To map the NS5 residues that are critical for the interactions, we performed site-direct mutagenesis in segment 3 of the interaction domain (ID) and confirmed the interaction using in vitro assays and in vivo coimmunoprecipitation. The significance of eIF3L for YFV replication was investigated using eIF3L overexpression and RNA interference.ResultsIn this work, we describe and characterize the interaction of NS5 with the translation factor eIF3L. The interaction between NS5 and eIF3L was confirmed using in vitro binding and in vivo coimmunoprecipitation assays. This interaction occurs at a region (the interaction domain of the RNApol domain) that is conserved in several flaviviruses and that is, therefore, likely to be relevant to the genus. eIF3L overexpression and plaque reduction assays showed a slight effect on YFV replication, indicating that the interaction of eIF3L with YFV NS5 may play a role in YFV replication.ConclusionsAlthough the precise function of eIF3L on interactions with viral proteins is not entirely understood, these results indicate an interaction of eIF3L with YF NS5 and that eIF3L overexpression facilitates translation, which has potential implications for virus replication.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The eukaryotic translation initiation factor 3 subunit L protein interacts with FlavivirusNS5 and may modulate yellow fever virus replication

Morais

Terzian

Duarte

et al. 2013

Virol J

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“…It has been reported that, during viral replication, the methyltransferase domains of the flavivirus NS5 proteins recruit cellular factors kinases (CK1 and PKG), 46,47 mitochondrial trifunctional protein (MTP), 48 and PSD-95/Dlg/ ZO-1 proteins, 49,50 while the RdRp domains can interact with the nuclear import receptors importin-α and importin-β, 43,51 cyclophilin A, 52 heat shock protein 70 (Hsp70), 53 protein kinase G (PKG), 40 L subunit of human eukaryotic translation initiation factor 3 (eIF3L), 54 and small nuclear ribonucleoprotein U1A. 55 These factors can enhance formation of the replication complex, RNA stability, genome translation, and/or posttranslational modification. 56,57 Considering the remarkable difference in YFV transmission cycles between Africa and South America, 58,59 the existence of the adaptive changes might favor the interaction between NS5 and cellular factors from different host and (or) vector.…”

Section: Discussionmentioning

confidence: 99%

Adaptive Diversification Between Yellow Fever Virus West African and South American Lineages: A Genome-Wide Study

Yang

2017

The American Society of Tropical Medicine and Hygiene

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Abstract. Yellow fever virus (YFV) has emerged as the causative agent of a vector-borne disease with devastating mortality in the tropics of Africa and the Americas. YFV phylogenies indicate that the isolates collected from West Africa, East and Central Africa, and South America cluster into different lineages and the virus spread into the Americas from Africa. To determine the nature of genetic variation accompanying the intercontinental epidemic, we performed a genome-wide evolutionary study on the West African and South American lineages of YFV. Our results reveal that adaptive genetic diversification has occurred on viral nonstructural protein 5 (NS5), which is crucially required for viral genome replication, in the early epidemic phase of these currently circulating lineages. Furthermore, major amino acid changes relevant to the adaptive diversification generally cluster in different structural regions of NS5 in a lineage-specific manner. These results suggest that YFV has experienced adaptive diversification in the epidemic spread between the continents and shed insights into the genetic determinants of such diversification, which might be beneficial for understanding the emergence and re-emergence of yellow fever as an important global public health issue.

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“…Interaction of NS5 with the host protein U1A occurs at a site that is highly conserved across various flaviviruses, and may represent potential broad-spectrum inhibition of viral replication (Bronzoni et al, 2011). Knowledge of these various cellular components that are important in virus replication may result in novel targets for inhibition of YFV and also strengthens the case to develop broad-spectrum inhibitors of flavivirus NS3 and NS5.…”

Section: Targeting the Virusmentioning

confidence: 99%

Experimental therapies for yellow fever

Julander

2013

Antiviral Research

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A number of viruses in the family Flaviviridae are the focus of efforts to develop effective antiviral therapies. Success has been achieved with inhibitors for the treatment of hepatitis C, and there is interest in clinical trials of drugs against dengue fever. Antiviral therapies have also been evaluated in patients with Japanese encephalitis and West Nile encephalitis. However, no treatment has been developed against the prototype flavivirus, yellow fever virus (YFV). Despite the availability of the live, attenuated 17D vaccine, thousands of cases of YF continue to occur each year in Africa and South America, with a significant mortality rate. In addition, a small number of vaccinees develop severe systemic infections with the 17D virus. This paper reviews current efforts to develop antiviral therapies, either directly targeting the virus or blocking detrimental host responses to infection.

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The small nuclear ribonucleoprotein U1A interacts with NS5 from yellow fever virus

Cited by 7 publications

References 38 publications

The eukaryotic translation initiation factor 3 subunit L protein interacts with FlavivirusNS5 and may modulate yellow fever virus replication

The eukaryotic translation initiation factor 3 subunit L protein interacts with FlavivirusNS5 and may modulate yellow fever virus replication

Adaptive Diversification Between Yellow Fever Virus West African and South American Lineages: A Genome-Wide Study

Experimental therapies for yellow fever

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