Influenza A Virus Infection of Human Respiratory Cells Induces Primary MicroRNA Expression

Buggele, William A.; Johnson, Karen E.; Horvath, Curt M.

doi:10.1074/jbc.m112.387670

Cited by 107 publications

(99 citation statements)

References 52 publications

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“…cluding IAV-infected A549 and BEAS-2B cells, but they detected miRNAs beginning only at 8 h postinfection (23). Furthermore, many studies have focused mainly on the regulation of antiviral responses by the miRNA machinery in the cells infected with viruses, including IAV (31).…”

Section: Discussionmentioning

confidence: 99%

“…1). Recent studies have demonstrated the changes in miRNA expression that are directed by IAV infection (23,25). Buggele et al revealed the induction of primary miRNA expression in human respiratory cell lines, incells were infected with PR8 virus at an MOI of 3.0, and the mRNA expression levels of GALNT1, GALNT2, GALNT6, and GALNT7 were monitored at the indicated times by real-time RT-PCR.…”

Section: Discussionmentioning

confidence: 99%

“…An increasing number of studies have suggested that cellular miRNAs play an important role in various host cell responses to viral infection (23)(24)(25).…”

Section: Downregulation Of Mirnas Targeting Galnt3 Mrna During the Eamentioning

confidence: 99%

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Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Nakamura

Horie

Daidoji

et al. 2016

J Virol

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Influenza A virus (IAV) affects the upper and lower respiratory tracts and rapidly induces the expression of mucins, which are common O-glycosylated proteins, on the epithelial surfaces of the respiratory tract. Although mucin production is associated with the inhibition of virus transmission as well as characteristic clinical symptoms, little is known regarding how mucins are produced on the surfaces of respiratory epithelial cells and how they affect IAV replication. In this study, we found that two microRNAs (miRNAs), miR-17-3p and miR-221, which target GalNAc transferase 3 (GALNT3) mRNA, are rapidly downregulated in human alveolar basal epithelial cells during the early stage of IAV infection. We demonstrated that the expression of GALNT3 mRNA is upregulated in an IAV replication-dependent fashion and leads to mucin production in bronchial epithelial cells. A lectin microarray analysis revealed that the stable expression of GALNT3 by human alveolar basal epithelial cells induces mucin-type O-glycosylation modifications similar to those present in IAV-infected cells, suggesting that GALNT3 promotes mucin-type O-linked glycosylation in IAV-infected cells. Notably, analyses using short interfering RNAs and miRNA mimics showed that GALNT3 knockdown significantly reduces IAV replication. Furthermore, IAV replication was markedly decreased in embryonic fibroblast cells obtained from galnt3-knockout mice. Interestingly, IAV-infected galnt3-knockout mice exhibited high mortality and severe pathological alterations in the lungs compared to those of wild-type mice. Our results demonstrate not only the molecular mechanism underlying rapid mucin production during IAV infection but also the contribution of O-linked glycosylation to the replication and propagation of IAV in lung cells. IMPORTANCEViral infections that affect the upper or lower respiratory tracts, such as IAV, rapidly induce mucin production on the epithelial surfaces of respiratory cells. However, the details of how mucin-type O-linked glycosylation is initiated by IAV infection and how mucin production affects viral replication have not yet been elucidated. In this study, we show that levels of two miRNAs that target the UDP-GalNAc transferase GALNT3 are markedly decreased during the early stage of IAV infection, resulting in the upregulation of GALNT3 mRNA. We also demonstrate that the expression of GALNT3 initiates mucin production and affects IAV replication in infected cells. This is the first report demonstrating the mechanism underlying the miRNA-mediated initiation of mucin-type O-glycosylation in IAV-infected cells and its role in viral replication. Our results have broad implications for understanding IAV replication and suggest a strategy for the development of novel anti-influenza approaches.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Nakamura

Horie

Daidoji

et al. 2016

J Virol

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“…Influenza virus uses small RNA in regulation of virus replication and in modulation of the innate immune signalling system of the host (Perez et al, 2010;Buggele et al, 2012). shRNAs and siRNAs provide the valuable tools for identification of host proteins involved in viral replication and for an alternative disease intervention approach to controlling influenza virus replication (Hirsch, 2010;.…”

Section: Pathway Of Rnaimentioning

confidence: 99%

“…Gene expression profiling identified 26 cellular mRNAs targeted by these miRNAs, including IRAK1, MAPK3, and other components of the innate immune signalling system. (Buggele et al, 2012). MAPK3 and IRAK1 are targeted for mRNA degradation and protein inhibition by the combinatorial effect of miR-132 and miR-1275, and miR-146a and miR-1275, respectively.…”

Section: Cellular Mirna and Mirna Inhibitorsmentioning

confidence: 99%

Role and application of RNA interference in replication of influenza viruses

Betáková¹,

Švančarová²

2013

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Summary. -RNA interference (RNAi) is a naturally occurring endogenous biological post-transcriptional cellular mechanism that regulates RNA expression. Small interfering RNAs (siRNAs), mediators of RNAi, are short (19-26nt), double-stranded RNA duplexes that inhibit gene expression by inducing sequence-specific degradation of homologous messenger RNA (mRNA). Influenza virus infection is a major public health problem, causing hundreds of thousands of deaths worldwide each year. RNAi have provided a means to performing genome-wide screens to determine and validate host cell genes that may be required for influenza replication and treatment with siRNA specific to regions of the influenza genes which can inhibit influenza virus replication. Moreover, influenza virus is using small RNA in the regulation of virus replication and in modulation of the innate immune signalling system of the host. Keywords: influenza virus; RNA interference; siRNA; miRNA; replication; transcription E-mail: virubeta@savba.sk; phone: +421-2-59302440. Abbreviations: ADAMTS7 = ADAM metallopeptidase with thrombospondin type 1 motif7, CPE = carboxypeptidase E; cRNA = complementary RNA; DPP3 = dipeptidyl-peptidase 3; dsR-NA = double-stranded RNA; HA = hemagglutinin; IL = interleukin; INF = interferon; MLC = myosin light chain; mRNA = messenger RNA; miRNA = micro RNA; MST1 = macrophage stimulating 1; M1 = matrix protein; NA = neuraminidase; NCR = noncoding region; NEP = nuclear export protein; NP = nucleoprotein; NS1 = nonstructural protein; PA = polymerase acidic protein; PB1 = polymerase basic protein 1; PB2 = polymerase basic protein 2; pre-miRNA = precursor-micro RNA; pri-miRNA = primary-micro RNA; PRSS12 = neurotrypsin, motopsin; RdRp = RNA-dependent RNA polymerase; RISC = RNA-induced silencing complex; RNA = ribonucleic acid, RNAi = RNA interference; shRNA = short hairpin RNA; siRNA = small interfering RNA; svRNA = small viral RNA; TNF = tumour necrosis factor; vRNA = viral RNA; WHO = World Health Organization

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Temperature‐sensitive miR‐483 is a conserved regulator of recombinant protein and viral vector production in mammalian cells

Emmerling

Fischer

Stiefel

et al. 2015

Biotech & Bioengineering

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Cell engineering and bioprocess optimizations such as low temperature cultivation represent powerful tools to improve cellular performance and product yields of mammalian production cells. Besides monoclonal antibodies (mABs), novel biotherapeutic formats such as viral vectors will gain increasing importance. Here, we demonstrate that similar to Chinese hamster ovary (CHO) cells, product yields of recombinant adeno-associated virus (rAAV) producing HeLa cells can be markedly increased by low temperature cultivation. MicroRNAs (miRNAs) are small non-coding RNAs that critically regulate cell phenotypes. We thus investigated differential miRNA expression in response to mild hypothermia in CHO and HeLa production cells. We discovered miR-483 to be substantially up-regulated upon temperature down-shift in both cell types. Functional validation experiments revealed that introduction of miR-483 mimics led to a significant increase in both rAAV and mAB production in HeLa and CHO cells, respectively. Furthermore, inhibition of miR-483 up-regulation during mild hypothermia significantly decreased product yields, suggesting that miR-483 is a key regulator of cellular productivity in mammalian cells. In addition, miRNA target gene identification indicated that miR-483 might regulate genes directly involved in cellular survival and protein expression. Our results highlight that miR-483 is a valuable tool for product-independent engineering of mammalian production cells.

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Influenza A Virus Infection of Human Respiratory Cells Induces Primary MicroRNA Expression

Cited by 107 publications

References 52 publications

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Role and application of RNA interference in replication of influenza viruses

Temperature‐sensitive miR‐483 is a conserved regulator of recombinant protein and viral vector production in mammalian cells

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