Small RNA Profiling of Influenza A Virus-Infected Cells Identifies miR-449b as a Regulator of Histone Deacetylase 1 and Interferon Beta

Buggele, William A.; Krause, Katherine E.; Horvath, Curt M.

doi:10.1371/journal.pone.0076560

Cited by 42 publications

(32 citation statements)

References 57 publications

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“…IAV downregulates HDAC1 expression at both the mRNA and the polypeptide level. The reduction in HDAC1 mRNA level in IAVinfected cells observed here is consistent with a recent microarraybased gene expression profiling study (38). By using mainly a luciferase reporter assay and quantitative real-time PCR, Buggele et al (38) demonstrated that IAV induces host microRNA, miR449b that targets the 3= untranslated region of HDAC1 mRNA, and when added exogenously, miR-449b further reduced HDAC1 mRNA level in infected cells.…”

Section: Discussionsupporting

confidence: 90%

“…The reduction in HDAC1 mRNA level in IAVinfected cells observed here is consistent with a recent microarraybased gene expression profiling study (38). By using mainly a luciferase reporter assay and quantitative real-time PCR, Buggele et al (38) demonstrated that IAV induces host microRNA, miR449b that targets the 3= untranslated region of HDAC1 mRNA, and when added exogenously, miR-449b further reduced HDAC1 mRNA level in infected cells. However, they did not determine HDAC1 polypeptide level in response to the direct IAV infection and could not establish a direct anti-IAV role of miR-449b or HDAC1 since the depletion or overexpression of miR-449b did not have an effect on IAV infection (38).…”

Section: Discussionsupporting

confidence: 90%

“…By using mainly a luciferase reporter assay and quantitative real-time PCR, Buggele et al (38) demonstrated that IAV induces host microRNA, miR449b that targets the 3= untranslated region of HDAC1 mRNA, and when added exogenously, miR-449b further reduced HDAC1 mRNA level in infected cells. However, they did not determine HDAC1 polypeptide level in response to the direct IAV infection and could not establish a direct anti-IAV role of miR-449b or HDAC1 since the depletion or overexpression of miR-449b did not have an effect on IAV infection (38). Here, we demonstrated that IAV also reduces the HDAC1 polypeptide level in infected cells by promoting its degradation by a proteasomal pathway.…”

Section: Discussionmentioning

confidence: 99%

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Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

Nagesh

Husain

2016

J Virol

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Viruses dysregulate the host factors that inhibit virus infection. Here, we demonstrate that human enzyme, histone deacetylase 1 (HDAC1) is a new class of host factor that inhibits influenza A virus (IAV) infection, and IAV dysregulates HDAC1 to efficiently replicate in epithelial cells. A time-dependent decrease in HDAC1 polypeptide level was observed in IAV-infected cells, reducing to <50% by 24 h of infection. A further depletion (97%) of HDAC1 expression by RNA interference increased the IAV growth kinetics, increasing it by >3-fold by 24 h and by >6-fold by 48 h of infection. Conversely, overexpression of HDAC1 decreased the IAV infection by >2-fold. Likewise, a time-dependent decrease in HDAC1 activity, albeit with slightly different kinetics to HDAC1 polypeptide reduction, was observed in infected cells. Nevertheless, a further inhibition of deacetylase activity increased IAV infection in a dose-dependent manner. HDAC1 is an important host deacetylase and, in addition to its role as a transcription repressor, HDAC1 has been lately described as a coactivator of type I interferon response. Consistent with this property, we found that inhibition of deacetylase activity either decreased or abolished the phosphorylation of signal transducer and activator of transcription I (STAT1) and expression of interferon-stimulated genes, IFITM3, ISG15, and viperin in IAV-infected cells. Furthermore, the knockdown of HDAC1 expression in infected cells decreased viperin expression by 58% and, conversely, the overexpression of HDAC1 increased it by 55%, indicating that HDAC1 is a component of IAV-induced host type I interferon antiviral response. IMPORTANCEInfluenza A virus (IAV) continues to significantly impact global public health by causing regular seasonal epidemics, occasional pandemics, and zoonotic outbreaks. IAV is among the successful human viral pathogens that has evolved various strategies to evade host defenses, prevent the development of a universal vaccine, and acquire antiviral drug resistance. A comprehensive knowledge of IAV-host interactions is needed to develop a novel and alternative anti-IAV strategy. Host produces a variety of factors that are able to fight IAV infection by employing various mechanisms. However, the full repertoire of anti-IAV host factors and their antiviral mechanisms has yet to be identified. We have identified here a new host factor, histone deacetylase 1 (HDAC1) that inhibits IAV infection. We demonstrate that HDAC1 is a component of host innate antiviral response against IAV, and IAV undermines HDAC1 to limit its role in antiviral response. Influenza A virus (IAV), a prototypic member of family Orthomyxoviridae, has been a successful human respiratory pathogen. IAV has prevented the development of a universal vaccine so far and rendered the currently approved anti-influenza virus drugs almost ineffective. A unique genetic make-up comprising of a segmented RNA genome and a broad host range of humans, birds, pigs, dogs, cats, horses, seals, and bats allows the regular emer...

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

Nagesh

Husain

2016

J Virol

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“…miRs cause degradation of target mRNAs through perfect and imperfect complementation between a seed sequence in the miR and target sequences, typically located within the 3=UTR or sometimes the 5=UTR of the target mRNA (39). Some miRs directly target viral mRNAs, while others act indirectly via cellular genes that in turn impact viral gene expression (40)(41)(42)(43). For example, miR-155 inhibits Epstein-Bar virus (EBV) lytic infection and plays a role in maintenance of latency (44), miR-498 and miR-330d reduce Kaposi's sarcoma-associated herpesvirus (KSHV) replication by targeting the viral RTA (43,45), and miR-100 and miR-101 attenuate HCMV replication via the mTOR pathway (41).…”

mentioning

confidence: 99%

MicroRNA miR-21 Attenuates Human Cytomegalovirus Replication in Neural Cells by Targeting Cdc25a

Liu

et al. 2015

J Virol

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Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily manifesting as neurological disorders. HCMV infection alters expression of cellular microRNAs (miRs These results suggest that Cdc25a promotes HCMV replication and elevation of Cdc25a levels after HCMV infection are due in part to HCMV-mediated repression of miR-21. Thus, miR-21 is an intrinsic antiviral factor that is modulated by HCMV infection. This suggests a role for miR-21 downregulation in the neuropathogenesis of HCMV infection of the developing CNS. IMPORTANCEHuman cytomegalovirus (HCMV) is a ubiquitous pathogen and has very high prevalence among population, especially in China, and congenital HCMV infection is a major cause for birth defects. Elucidating virus-host interactions that govern HCMV replication in neuronal cells is critical to understanding the neuropathogenesis of birth defects resulting from congenital infection. In this study, we confirm that HCMV infection downregulates miR-21 but upregulates Cdc25a. Further determined the negative effects of cellular miRNA miR-21 on HCMV replication in neural progenitor/stem cells and U-251MG glioblastoma/astrocytoma cells. More importantly, our results provide the first evidence that miR-21 negatively regulates HCMV replication by targeting Cdc25a, a vital cell cycle regulator. We further found that viral gene products of IE1, pp71, and UL26 play roles in inhibiting miR-21 expression, which in turn causes increases in Cdc25a and benefits HCMV replication. Thus, miR-21 appears to be an intrinsic antiviral factor that represents a potential target for therapeutic intervention.

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“…In addition, microRNAs (miRNAs) have been found to play important roles in the virus life cycle. It has been confirmed that miRNAs can modulate the influenza virus life cycle by directly repressing viral protein expression or controlling the host immune response (Buggele et al, 2013;Song et al, 2010). In return, it has been reported that many viruses have adapted strategies to eliminate miRNAs harmful for their replication (Andersson et al, 2005;Lu & Cullen, 2004;Marcinowski et al, 2012).…”

Section: Introductionmentioning

confidence: 98%

MicroRNA-33a disturbs influenza A virus replication by targeting ARCN1 and inhibiting viral ribonucleoprotein activity

Jiang

Lai

et al. 2016

Journal of General Virology

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In order to explore the roles of microRNA(s) [miRNA(s)] in the influenza A virus life cycle, we compared the miRNA profiles of 293T and HeLa cell lines, as influenza A virus can replicate efficiently in 293T cells but only poorly in HeLa cells. We analysed differentially expressed miRNAs and identified five, including miR-33a, that could disturb influenza A virus replication significantly. Using TargetScan analysis, we found that ARCN1 could be a potential target of miR-33a. To confirm whether miR-33a could truly target ARCN1, we generated a luciferase reporter for the ARCN1 39 untranslated region (UTR) and performed a luciferase assay. The data indicated that miR-33a could suppress the luciferase activity of the reporter for the ARCN1 39 UTR but not a reporter in which the predicted miR-33a targeting sites on ARCN1 39 UTR were mutated. We performed immunoblotting to confirm that miR-33a could downregulate the protein level of ARCN1. Consistently, the level of ARCN1 protein in HeLa cells was significantly lower than that in 293T cells. We also demonstrated that ectopic expression of ARCN1 could partially rescue the inhibitory effect of miR-33a on virus replication. Furthermore, we demonstrated that miR-33a could impede virus replication at the stage of virus internalization, which was similar to the pattern for knockdown of ARCN1, indicating that miR-33a inhibits influenza virus infection by suppressing ARCN1 expression. In addition, we found that miR-33a could also weaken the viral ribonucleoprotein activity in an ARCN1-independent manner. In conclusion, we found that miR-33a is a novel inhibitory factor for influenza A virus replication.

show abstract

Small RNA Profiling of Influenza A Virus-Infected Cells Identifies miR-449b as a Regulator of Histone Deacetylase 1 and Interferon Beta

Cited by 42 publications

References 57 publications

Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

MicroRNA miR-21 Attenuates Human Cytomegalovirus Replication in Neural Cells by Targeting Cdc25a

MicroRNA-33a disturbs influenza A virus replication by targeting ARCN1 and inhibiting viral ribonucleoprotein activity

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