Poly-ADP Ribosyl Polymerase 1 (PARP1) Regulates Influenza A Virus Polymerase

Westera, Liset; Jennings, Alisha M.; Maamary, Jad; Schwemmle, Martin; García‐Sastre, Adolfo; Bortz, Eric

doi:10.1155/2019/8512363

Cited by 16 publications

(18 citation statements)

References 59 publications

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“…6C). While these results are not statistically significant under our experimental conditions, they could correspond to the known effects of IAV polymerase interacting with PARP1 (23). It is likely that the presence of PARP1 in the nucleus and cytoplasm could also have different but necessary effects for robust influenza virus replication.…”

Section: Discussioncontrasting

confidence: 61%

“…PARP1 and PARP13.1 have been previously shown to regulate the function of influenza viral polymerases (22)(23)(24). However, under our experimental settings, PARP1 bound to HA during IAV infection (Fig.…”

Section: Discussionmentioning

confidence: 67%

“…Of note, PARP1 is well-known as a regulator during tumor development (17), and a PARP1 inhibitor is approved as a therapeutic option for patients with cancers derived from BRCA germ line mutations, such as breast or ovarian cancer. PARP1 and PARP13.1 have been shown to regulate influenza A virus polymerase activity, which in turn affects IAV replication (22)(23)(24). Additionally, PARP1 depletion in human cancer cells induces the expression of interferon-stimulated genes (ISGs), suggesting the possible involvement of PARP1 in IFN signaling (25).…”

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confidence: 99%

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PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor

Xia

Wolf

Sun

et al. 2020

J Virol

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Influenza A virus (IAV) utilizes multiple strategies to confront or evade host type I interferon (IFN)-mediated antiviral responses in order to enhance its own propagation within the host. One such strategy is to induce the degradation of type I IFN receptor 1 (IFNAR1) by utilizing viral hemagglutinin (HA). However, the molecular mechanism behind this process is poorly understood. Here, we report that a cellular protein, poly(ADP-ribose) polymerase 1 (PARP1), plays a critical role in mediating IAV HA-induced degradation of IFNAR1. We identified PARP1 as an interacting partner for IAV HA through mass spectrometry analysis. This interaction was confirmed by coimmunoprecipitation analyses. Furthermore, confocal fluorescence microscopy showed altered localization of endogenous PARP1 upon transient IAV HA expression or during IAV infection. Knockdown or inhibition of PARP1 rescued IFNAR1 levels upon IAV infection or HA expression, exemplifying the importance of PARP1 for IAV-induced reduction of IFNAR1. Notably, PARP1 was crucial for the robust replication of IAV, which was associated with regulation of the type I IFN receptor signaling pathway. These results indicate that PARP1 promotes IAV replication by controlling viral HA-induced degradation of host type I IFN receptor. Altogether, these findings provide novel insight into interactions between influenza virus and the host innate immune response and reveal a new function for PARP1 during influenza virus infection. IMPORTANCE Influenza A virus (IAV) infections cause seasonal and pandemic influenza outbreaks, which pose a devastating global health concern. Despite the availability of antivirals against influenza, new IAV strains continue to persist by overcoming the therapeutics. Therefore, much emphasis in the field is placed on identifying new therapeutic targets that can more effectively control influenza. IAV utilizes several tactics to evade host innate immunity, which include the evasion of antiviral type I interferon (IFN) responses. Degradation of type I IFN receptor (IFNAR) is one known method of subversion, but the molecular mechanism for IFNAR downregulation during IAV infection remains unclear. Here, we have found that a host protein, poly(ADP-ribose) polymerase 1 (PARP1), facilitates IFNAR degradation and accelerates IAV replication. The findings reveal a novel cellular target for the potential development of antivirals against influenza, as well as expand our base of knowledge regarding interactions between influenza and the host innate immunity.

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Section: Discussioncontrasting

confidence: 61%

Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 99%

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PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor

Xia

Wolf

Sun

et al. 2020

J Virol

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“…There are also some differences in gene expression observed such as CD40 and PARP1 up-regulated in vaccinated samples. CD40 has previously been shown to regulate immune response and promotes protection against the virus (58, 59) while PARP1 has been highlighted as a host factor that can regulate the polymerase activity of influenza (60). In Figure 5, the genes in our vaccine list in the RIG-I-like receptor signaling pathway are down-regulated, compared to influenza infected subjects (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Microarray Gene Expression Dataset Re-analysis Reveals Variability in Influenza Infection and Vaccination

2019

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Influenza, a communicable disease, affects thousands of people worldwide. Young children, elderly, immunocompromised individuals and pregnant women are at higher risk for being infected by the influenza virus. Our study aims to highlight differentially expressed genes in influenza disease compared to influenza vaccination, including variability due to age and sex. To accomplish our goals, we conducted a meta-analysis using publicly available microarray expression data. Our inclusion criteria included subjects with influenza, subjects who received the influenza vaccine and healthy controls. We curated 18 microarray datasets for a total of 3,481 samples (1,277 controls, 297 influenza infection, 1,907 influenza vaccination). We pre-processed the raw microarray expression data in R using packages available to pre-process Affymetrix and Illumina microarray platforms. We used a Box-Cox power transformation of the data prior to our down-stream analysis to identify differentially expressed genes. Statistical analyses were based on linear mixed effects model with all study factors and successive likelihood ratio tests (LRT) to identify differentially-expressed genes. We filtered LRT results by disease (Bonferroni adjusted p < 0.05) and used a two-tailed 10% quantile cutoff to identify biologically significant genes. Furthermore, we assessed age and sex effects on the disease genes by filtering for genes with a statistically significant (Bonferroni adjusted p < 0.05) interaction between disease and age, and disease and sex. We identified 4,889 statistically significant genes when we filtered the LRT results by disease factor, and gene enrichment analysis (gene ontology and pathways) included innate immune response, viral process, defense response to virus, Hematopoietic cell lineage and NF-kappa B signaling pathway. Our quantile filtered gene lists comprised of 978 genes each associated with influenza infection and vaccination. We also identified 907 and 48 genes with statistically significant (Bonferroni adjusted p < 0.05) disease-age and disease-sex interactions, respectively. Our meta-analysis approach highlights key gene signatures and their associated pathways for both influenza infection and vaccination. We also were able to identify genes with an age and sex effect. This gives potential for improving current vaccines and exploring genes that are expressed equally across ages when considering universal vaccinations for influenza.

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“…There are also some differences in gene expression observed such as CD40 and PARP1 up-regulated in vaccinated samples. CD40 has previously been shown to regulate immune response and promotes protection against the virus (41, 42) while PARP1 has been highlighted as a host factor that can regulate the polymerase activity of influenza (43). In Figure 5, the genes in our vaccine list in the RIG-I-like receptor signaling pathway are down-regulated, compared to influenza infected subjects (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Microarray Gene Expression Dataset Re-Analysis Reveals Variability in Influenza Infection and Vaccination

Rogers

Campos

Mias

2019

Preprint

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2Influenza, a communicable disease, affects thousands of people worldwide. Young children, 3 elderly, immunocompromised individuals and pregnant women are at higher risk for being 4 infected by the influenza virus. Our study aims to highlight differentially expressed genes in 5 influenza disease compared to influenza vaccination. We also investigate genetic variation 6 due to the age and sex of samples. To accomplish our goals, we conducted a meta-analysis 7 using publicly available microarray expression data. Our inclusion criteria included subjects with 8 influenza, subjects who received the influenza vaccine and healthy controls. We curated 18 9 microarray datasets for a total of 3,481 samples (1,277 controls, 297 influenza infection, 1,907 10 influenza vaccination). We pre-processed the raw microarray expression data in R using packages 11 available to pre-process Affymetrix and Illumina microarray platforms. We used a Box-Cox power 12 transformation of the data prior to our down-stream analysis to identify differentially expressed 13 genes. Statistical analyses were based on linear mixed effects model with all study factors and 14 successive likelihood ratio tests (LRT) to identify differentially-expressed genes. We filtered LRT 15 results by disease (Bonferroni adjusted p-value < 0.05) and used a two-tailed 10% quantile cutoff 16 to identify biologically significant genes. Furthermore, we assessed age and sex effects on the 17 disease genes by filtering for genes with a statistically significant (Bonferroni adjusted p-value < 18 0.05) interaction between disease and age, and disease and sex. We identified 4,889 statistically 19 significant genes when we filtered the LRT results by disease factor, and gene enrichment analysis 20 (gene ontology and pathways) included innate immune response, viral process, defense response 21 to virus, Hematopoietic cell lineage and NF-kappa B signaling pathway. Our quantile filtered gene 22 lists comprised of 978 genes each associated with influenza infection and vaccination. We also 23 identified 907 and 48 genes with statistically significant (Bonferroni adjusted p-value < 0.05) 24 disease-age and disease-sex interactions respectively. Our meta-analysis approach highlights 25 key gene signatures and their associated pathways for both influenza infection and vaccination. 26 1 Rogers LRK et al. Variability in Influenza Infection and VaccinationWe also were able to identify genes with an age and sex effect. This gives potential for improving 27 current vaccines and exploring genes that are expressed equally across ages when considering 28 universal vaccinations for influenza. 29 30

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Poly-ADP Ribosyl Polymerase 1 (PARP1) Regulates Influenza A Virus Polymerase

Cited by 16 publications

References 59 publications

PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor

PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor

Microarray Gene Expression Dataset Re-analysis Reveals Variability in Influenza Infection and Vaccination

Microarray Gene Expression Dataset Re-Analysis Reveals Variability in Influenza Infection and Vaccination

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