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1.
J Biol Chem ; 293(19): 7126-7138, 2018 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-29555684

RESUMO

Histone acetylation plays crucial roles in transcriptional regulation and chromatin organization. Viral RNA of the influenza virus interacts with its nucleoprotein (NP), whose function corresponds to that of eukaryotic histones. NP regulates viral replication and has been shown to undergo acetylation by the cAMP-response element (CRE)-binding protein (CBP) from the host. However, whether NP is the target of other host acetyltransferases is unknown. Here, we show that influenza virus NP undergoes acetylation by the two host acetyltransferases GCN5 and P300/CBP-associated factor (PCAF) and that this modification affects viral polymerase activities. Western blot analysis with anti-acetyl-lysine antibody on cultured A549 human lung adenocarcinoma epithelial cells infected with different influenza virus strains indicated acetylation of the viral NP. A series of biochemical analyses disclosed that the host lysine acetyltransferases GCN5 and PCAF acetylate NP in vitro MS experiments identified three lysine residues as acetylation targets in the host cells and suggested that Lys-31 and Lys-90 are acetylated by PCAF and GCN5, respectively. RNAi-mediated silencing of GCN5 and PCAF did not change acetylation levels of NP. However, interestingly, viral polymerase activities were increased by the PCAF silencing and were decreased by the GCN5 silencing, suggesting that acetylation of the Lys-31 and Lys-90 residues has opposing effects on viral replication. Our findings suggest that epigenetic control of NP via acetylation by host acetyltransferases contributes to regulation of polymerase activity in the influenza A virus.


Assuntos
Histona Acetiltransferases/metabolismo , Vírus da Influenza A/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas do Core Viral/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Células A549 , Acetilação , Sequência de Aminoácidos , Western Blotting , Cromatografia Líquida , Epigênese Genética , Células Epiteliais/virologia , Histona Acetiltransferases/genética , Humanos , Vírus da Influenza A/enzimologia , Vírus da Influenza A/genética , Vírus da Influenza A/fisiologia , Lisina/metabolismo , Proteínas do Nucleocapsídeo , Processamento de Proteína Pós-Traducional , Interferência de RNA , RNA Viral/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Espectrometria de Massas em Tandem , Transcrição Gênica , Proteínas do Core Viral/química , Proteínas do Core Viral/genética , Replicação Viral , Fatores de Transcrição de p300-CBP/genética
2.
J Biol Chem ; 290(46): 28001-17, 2015 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-26446794

RESUMO

Influenza represents a substantial threat to human health and requires novel therapeutic approaches. Bakuchiol is a phenolic isoprenoid compound present in Babchi (Psoralea corylifolia L.) seeds. We examined the anti-influenza viral activity of synthetic bakuchiol using Madin-Darby canine kidney cells. We found that the naturally occurring form, (+)-(S)-bakuchiol, and its enantiomer, (-)-(R)-bakuchiol, inhibited influenza A viral infection and growth and reduced the expression of viral mRNAs and proteins in these cells. Furthermore, these compounds markedly reduced the mRNA expression of the host cell influenza A virus-induced immune response genes, interferon-ß and myxovirus-resistant protein 1. Interestingly, (+)-(S)-bakuchiol had greater efficacy than (-)-(R)-bakuchiol, indicating that chirality influenced anti-influenza virus activity. In vitro studies indicated that bakuchiol did not strongly inhibit the activities of influenza surface proteins or the M2 ion channel, expressed in Chinese hamster ovary cells. Analysis of luciferase reporter assay data unexpectedly indicated that bakuchiol may induce some host cell factor(s) that inhibited firefly and Renilla luciferases. Next generation sequencing and KeyMolnet analysis of influenza A virus-infected and non-infected cells exposed to bakuchiol revealed activation of transcriptional regulation by nuclear factor erythroid 2-related factor (Nrf), and an Nrf2 reporter assay showed that (+)-(S)-bakuchiol activated Nrf2. Additionally, (+)-(S)-bakuchiol up-regulated the mRNA levels of two Nrf2-induced genes, NAD(P)H quinone oxidoreductase 1 and glutathione S-transferase A3. These findings demonstrated that bakuchiol had enantiomer-selective anti-influenza viral activity involving a novel effect on the host cell oxidative stress response.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Influenza Humana/virologia , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Terpenos/farmacologia , Animais , Antivirais/química , Células CHO , Cricetinae , Cricetulus , Cães , Glutationa Transferase/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Interferon beta/metabolismo , Células Madin Darby de Rim Canino , NAD(P)H Desidrogenase (Quinona) , Fator 2 Relacionado a NF-E2/metabolismo , Infecções por Orthomyxoviridae/virologia , Fenóis/química , RNA Mensageiro/efeitos dos fármacos , RNA Viral/efeitos dos fármacos , Terpenos/química , Transcrição Gênica
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