{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:50:38Z","timestamp":1784825438800,"version":"3.55.0"},"reference-count":125,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,3,26]],"date-time":"2020-03-26T00:00:00Z","timestamp":1585180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI129988"],"award-info":[{"award-number":["R01AI129988"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Influenza A viruses (IAVs) are a significant human pathogen that cause seasonal epidemics and occasional pandemics. Avian waterfowl are the natural reservoir of IAVs, but a wide range of species can serve as hosts. Most IAV strains are adapted to one host species and avian strains of IAV replicate poorly in most mammalian hosts. Importantly, IAV polymerases from avian strains function poorly in mammalian cells but host adaptive mutations can restore activity. The 2009 pandemic H1N1 (H1N1pdm09) virus acquired multiple mutations in the PA gene that activated polymerase activity in mammalian cells, even in the absence of previously identified host adaptive mutations in other polymerase genes. These mutations in PA localize within different regions of the protein suggesting multiple mechanisms exist to activate polymerase activity. Additionally, an immunomodulatory protein, PA-X, is expressed from the PA gene segment. PA-X expression is conserved amongst many IAV strains but activity varies between viruses specific for different hosts, suggesting that PA-X also plays a role in host adaptation. Here, we review the role of PA in the emergence of currently circulating H1N1pdm09 viruses and the most recent studies of host adaptive mutations in the PA gene that modulate polymerase activity and PA-X function.<\/jats:p>","DOI":"10.3390\/v12040365","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T10:29:38Z","timestamp":1585650578000},"page":"365","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Key Role of the Influenza A Virus PA Gene Segment in the Emergence of Pandemic Viruses"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3318-0808","authenticated-orcid":false,"suffix":"IV","given":"Michael M.","family":"Lutz","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan M.","family":"Dunagan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kurebayashi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA"},{"name":"Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-shi 422-8526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Takimoto","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"D49","DOI":"10.1016\/j.vaccine.2008.07.039","article-title":"The biology of influenza viruses","volume":"26","author":"Bouvier","year":"2008","journal-title":"Vaccine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1128\/mr.56.1.152-179.1992","article-title":"Evolution and ecology of influenza A viruses","volume":"56","author":"Webster","year":"1992","journal-title":"Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.tim.2014.01.010","article-title":"Bat-derived influenza-like viruses H17N10 and H18N11","volume":"22","author":"Wu","year":"2014","journal-title":"Trends Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/s41579-018-0115-z","article-title":"Host and viral determinants of influenza A virus species specificity","volume":"17","author":"Long","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/BF01718315","article-title":"Influenza virus PB1 protein is the minimal and essential subunit of RNA polymerase","volume":"141","author":"Kobayashi","year":"1996","journal-title":"Arch. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41586-019-1530-7","article-title":"Structures of influenza A virus RNA polymerase offer insight into viral genome replication","volume":"573","author":"Fan","year":"2019","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7200","DOI":"10.1128\/JVI.00980-13","article-title":"Adaptation of avian influenza A virus polymerase in mammals to overcome the host species barrier","volume":"87","author":"Manz","year":"2013","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/1743-422X-3-58","article-title":"Temperature sensitive influenza A virus genome replication results from low thermal stability of polymerase-cRNA complexes","volume":"3","author":"Dalton","year":"2006","journal-title":"Virol. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4603","DOI":"10.1128\/jvi.63.11.4603-4608.1989","article-title":"Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics","volume":"63","author":"Kawaoka","year":"1989","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/270617a0","article-title":"A single gene determines the host range of influenza virus","volume":"270","author":"Almond","year":"1977","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1128\/jvi.67.4.1761-1764.1993","article-title":"A single amino acid in the PB2 gene of influenza A virus is a determinant of host range","volume":"67","author":"Subbarao","year":"1993","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9978","DOI":"10.1128\/JVI.01134-10","article-title":"Evidence for avian and human host cell factors that affect the activity of influenza virus polymerase","volume":"84","author":"Moncorge","year":"2010","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature16474","article-title":"Species difference in ANP32A underlies influenza A virus polymerase host restriction","volume":"529","author":"Long","year":"2016","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1016\/j.celrep.2017.08.061","article-title":"Functional Insights into ANP32A-Dependent Influenza A Virus Polymerase Host Restriction","volume":"20","author":"Domingues","year":"2017","journal-title":"Cell Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Long, J.S., Idoko-Akoh, A., Mistry, B., Goldhill, D., Staller, E., Schreyer, J., Ross, C., Goodbourn, S., Shelton, H., and Skinner, M.A. (2019). Species specific differences in use of ANP32 proteins by influenza A virus. Elife, 8.","DOI":"10.7554\/eLife.45066"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8735","DOI":"10.1128\/JVI.00422-14","article-title":"PB2 mutations D701N and S714R promote adaptation of an influenza H5N1 virus to a mammalian host","volume":"88","author":"Otte","year":"2014","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gabriel, G., Herwig, A., and Klenk, H.D. (2008). Interaction of polymerase subunit PB2 and NP with importin alpha1 is a determinant of host range of influenza A virus. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.0040011"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/nsmb1212","article-title":"Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit","volume":"14","author":"Tarendeau","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1126\/science.1176225","article-title":"Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans","volume":"325","author":"Garten","year":"2009","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7020","DOI":"10.1128\/JVI.00522-11","article-title":"PA residues in the 2009 H1N1 pandemic influenza virus enhance avian influenza virus polymerase activity in mammalian cells","volume":"85","author":"Bussey","year":"2011","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1128\/JVI.06203-11","article-title":"Reassortment and mutation of the avian influenza virus polymerase PA subunit overcome species barriers","volume":"86","author":"Mehle","year":"2012","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhu, W., Zhu, Y., Qin, K., Yu, Z., Gao, R., Yu, H., Zhou, J., and Shu, Y. (2012). Mutations in polymerase genes enhanced the virulence of 2009 pandemic H1N1 influenza virus in mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033383"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"971","DOI":"10.2217\/fvl.15.62","article-title":"H5N1 influenza virulence, pathogenicity and transmissibility: What do we know?","volume":"10","author":"Neumann","year":"2015","journal-title":"Future Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10510","DOI":"10.1038\/srep10510","article-title":"Synergistic Effect of S224P and N383D Substitutions in the PA of H5N1 Avian Influenza Virus Contributes to Mammalian Adaptation","volume":"5","author":"Song","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/nrmicro.2016.87","article-title":"Influenza virus RNA polymerase: Insights into the mechanisms of viral RNA synthesis","volume":"14","author":"Fodor","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.virusres.2017.01.013","article-title":"Structural insights into RNA synthesis by the influenza virus transcription-replication machine","volume":"234","author":"Pflug","year":"2017","journal-title":"Virus Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/nature07745","article-title":"The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit","volume":"458","author":"Dias","year":"2009","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/nature07720","article-title":"Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site","volume":"458","author":"Yuan","year":"2009","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Huang, X., Kotlarek, D., and Worch, R. (2016). New Insight into Metal Ion-Driven Catalysis of Nucleic Acids by Influenza PA-Nter. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156972"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nature20594","article-title":"Structural basis of an essential interaction between influenza polymerase and Pol II CTD","volume":"541","author":"Lukarska","year":"2017","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1038\/nature07120","article-title":"Crystal structure of the polymerase PA(C)-PB1(N) complex from an avian influenza H5N1 virus","volume":"454","author":"He","year":"2008","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1038\/nature07225","article-title":"The structural basis for an essential subunit interaction in influenza virus RNA polymerase","volume":"454","author":"Obayashi","year":"2008","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.virol.2007.08.029","article-title":"Differential role of the influenza A virus polymerase PA subunit for vRNA and cRNA promoter binding","volume":"370","author":"Maier","year":"2008","journal-title":"Virology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"De Vlugt, C., Sikora, D., and Pelchat, M. (2018). Insight into Influenza: A Virus Cap-Snatching. Viruses, 10.","DOI":"10.3390\/v10110641"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Mailliot, J., and Martin, F. (2018). Viral internal ribosomal entry sites: Four classes for one goal. Wiley Interdiscip. Rev. RNA, 9.","DOI":"10.1002\/wrna.1458"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nrmicro2675","article-title":"Conventional and unconventional mechanisms for capping viral mRNA","volume":"10","author":"Decroly","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/0092-8674(81)90449-9","article-title":"A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription","volume":"23","author":"Plotch","year":"1981","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5812","DOI":"10.1128\/JVI.79.9.5812-5818.2005","article-title":"Association of the influenza A virus RNA-dependent RNA polymerase with cellular RNA polymerase II","volume":"79","author":"Engelhardt","year":"2005","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/nsmb.1421","article-title":"The structural basis for cap binding by influenza virus polymerase subunit PB2","volume":"15","author":"Guilligay","year":"2008","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1099\/0022-1317-75-1-29","article-title":"Complex structure of the nuclear translocation signal of influenza virus polymerase PA subunit","volume":"75","author":"Nieto","year":"1994","journal-title":"J. Gen. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9144","DOI":"10.1128\/JVI.78.17.9144-9153.2004","article-title":"The PA subunit is required for efficient nuclear accumulation of the PB1 subunit of the influenza A virus RNA polymerase complex","volume":"78","author":"Fodor","year":"2004","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/0168-1702(92)90031-4","article-title":"Nuclear transport of influenza virus polymerase PA protein","volume":"24","author":"Nieto","year":"1992","journal-title":"Virus Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/nature14008","article-title":"Structure of influenza A polymerase bound to the viral RNA promoter","volume":"516","author":"Pflug","year":"2014","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nature15525","article-title":"Crystal structure of the RNA-dependent RNA polymerase from influenza C virus","volume":"527","author":"Hengrung","year":"2015","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.molcel.2015.11.016","article-title":"Influenza Polymerase Can Adopt an Alternative Configuration Involving a Radical Repacking of PB2 Domains","volume":"61","author":"Thierry","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.molcel.2018.05.011","article-title":"A Mechanism for the Activation of the Influenza Virus Transcriptase","volume":"70","author":"Hengrung","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"21312","DOI":"10.1073\/pnas.0911915106","article-title":"Adaptive strategies of the influenza virus polymerase for replication in humans","volume":"106","author":"Mehle","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"13066","DOI":"10.1038\/s41598-018-31397-3","article-title":"Multiple polymerase gene mutations for human adaptation occurring in Asian H5N1 influenza virus clinical isolates","volume":"8","author":"Arai","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Qiang, X., and Kou, Z. (2019). Scoring amino acid mutation to predict pandemic risk of avian influenza virus. BMC Bioinform., 20.","DOI":"10.1186\/s12859-019-2770-0"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Miotto, O., Heiny, A.T., Albrecht, R., Garcia-Sastre, A., Tan, T.W., August, J.T., and Brusic, V. (2010). Complete-proteome mapping of human influenza A adaptive mutations: Implications for human transmissibility of zoonotic strains. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009025"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.3201\/eid1209.060276","article-title":"Genomic signatures of human versus avian influenza A viruses","volume":"12","author":"Chen","year":"2006","journal-title":"Emerg. Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10292","DOI":"10.1128\/JVI.00921-07","article-title":"Persistent Host Markers in Pandemic and H5N1 Influenza Viruses","volume":"81","author":"Finkelstein","year":"2007","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jprot.2016.01.018","article-title":"Host cell interactome of PA protein of H5N1 influenza A virus in chicken cells","volume":"136","author":"Wang","year":"2016","journal-title":"J. Proteom."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.chom.2014.11.002","article-title":"Influenza virus-host interactome screen as a platform for antiviral drug development","volume":"16","author":"Watanabe","year":"2014","journal-title":"Cell Host Microbe"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"739","DOI":"10.3389\/fmicb.2017.00739","article-title":"Generation and Comprehensive Analysis of Host Cell Interactome of the PA Protein of the Highly Pathogenic H5N1 Avian Influenza Virus in Mammalian Cells","volume":"8","author":"Gao","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"13876","DOI":"10.1038\/ncomms13876","article-title":"Comparative influenza protein interactomes identify the role of plakophilin 2 in virus restriction","volume":"8","author":"Wang","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.immuni.2015.12.017","article-title":"Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection","volume":"44","author":"Heaton","year":"2016","journal-title":"Immunity"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8569","DOI":"10.1128\/JVI.00496-11","article-title":"Comprehensive proteomic analysis of influenza virus polymerase complex reveals a novel association with mitochondrial proteins and RNA polymerase accessory factors","volume":"85","author":"Mattiacio","year":"2011","journal-title":"J. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"936","DOI":"10.3389\/fmicb.2018.00936","article-title":"Host Interaction Analysis of PA-N155 and PA-N182 in Chicken Cells Reveals an Essential Role of UBA52 for Replication of H5N1 Avian Influenza Virus","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1128\/JVI.00939-12","article-title":"Cellular protein HAX1 interacts with the influenza A virus PA polymerase subunit and impedes its nuclear translocation","volume":"87","author":"Hsu","year":"2013","journal-title":"J. Virol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"12062","DOI":"10.1128\/JVI.00684-11","article-title":"Cellular human CLE\/C14orf166 protein interacts with influenza virus polymerase and is required for viral replication","volume":"85","author":"Rodriguez","year":"2011","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"20744","DOI":"10.1038\/srep20744","article-title":"hCLE\/C14orf166, a cellular protein required for viral replication, is incorporated into influenza virus particles","volume":"6","author":"Pazo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5052","DOI":"10.1093\/nar\/gkv333","article-title":"Sequencing the cap-snatching repertoire of H1N1 influenza provides insight into the mechanism of viral transcription initiation","volume":"43","author":"Koppstein","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"6181","DOI":"10.1038\/srep06181","article-title":"Deep sequencing reveals the eight facets of the influenza A\/HongKong\/1\/1968 (H3N2) virus cap-snatching process","volume":"4","author":"Sikora","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1261\/rna.054221.115","article-title":"Influenza A virus preferentially snatches noncoding RNA caps","volume":"21","author":"Gu","year":"2015","journal-title":"RNA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1128\/JVI.03155-13","article-title":"Virulence-affecting amino acid changes in the PA protein of H7N9 influenza A viruses","volume":"88","author":"Yamayoshi","year":"2014","journal-title":"J. Virol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"37800","DOI":"10.1038\/srep37800","article-title":"Amino acid substitutions V63I or A37S\/I61T\/V63I\/V100A in the PA N-terminal domain increase the virulence of H7N7 influenza A virus","volume":"6","author":"Hu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"12325","DOI":"10.1128\/JVI.01373-09","article-title":"The polymerase acidic protein gene of influenza a virus contributes to pathogenicity in a mouse model","volume":"83","author":"Song","year":"2009","journal-title":"J. Virol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Slaine, P.D., MacRae, C., Kleer, M., Lamoureux, E., McAlpine, S., Warhuus, M., Comeau, A.M., McCormick, C., Hatchette, T., and Khaperskyy, D.A. (2018). Adaptive Mutations in Influenza A\/California\/07\/2009 Enhance Polymerase Activity and Infectious Virion Production. Viruses, 10.","DOI":"10.20944\/preprints201803.0149.v1"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8105","DOI":"10.1128\/JVI.00883-16","article-title":"Prevailing PA Mutation K356R in Avian Influenza H9N2 Virus Increases Mammalian Replication and Pathogenicity","volume":"90","author":"Xu","year":"2016","journal-title":"J. Virol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.virol.2017.06.020","article-title":"Influenza A virus cap-snatches host RNAs based on their abundance early after infection","volume":"509","author":"Sikora","year":"2017","journal-title":"Virology"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Oymans, J., and Te Velthuis, A.J.W. (2018). A Mechanism for Priming and Realignment during Influenza A Virus Replication. J. Virol., 92.","DOI":"10.1128\/JVI.01773-17"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.virol.2019.08.002","article-title":"Priming and realignment by the influenza a virus RdRp is dependent on the length of the host primers and the extent of base pairing to viral RNA","volume":"536","author":"Sikora","year":"2019","journal-title":"Virology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1099\/vir.0.033902-0","article-title":"Repetitive prime-and-realign mechanism converts short capped RNA leaders into longer ones that may be more suitable for elongation during rice stripe virus transcription initiation","volume":"93","author":"Yao","year":"2012","journal-title":"J. Gen. Virol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1101\/gad.200303.112","article-title":"The RNA polymerase II CTD coordinates transcription and RNA processing","volume":"26","author":"Hsin","year":"2012","journal-title":"Genes Dev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2922","DOI":"10.1101\/gad.1477006","article-title":"Phosphorylation and functions of the RNA polymerase II CTD","volume":"20","author":"Phatnani","year":"2006","journal-title":"Genes Dev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"18590","DOI":"10.1073\/pnas.0507415102","article-title":"The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host","volume":"102","author":"Gabriel","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"9601","DOI":"10.1128\/JVI.00666-07","article-title":"Differential polymerase activity in avian and mammalian cells determines host range of influenza virus","volume":"81","author":"Gabriel","year":"2007","journal-title":"J. Virol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"16616","DOI":"10.1038\/s41598-019-51877-4","article-title":"Synergistic PA and HA mutations confer mouse adaptation of a contemporary A\/H3N2 influenza virus","volume":"9","author":"Baz","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.virol.2017.02.008","article-title":"Selective incorporation of vRNP into influenza A virions determined by its specific interaction with M1 protein","volume":"505","author":"Chaimayo","year":"2017","journal-title":"Virology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"11525","DOI":"10.1073\/pnas.1001984107","article-title":"Influenza A virus-generated small RNAs regulate the switch from transcription to replication","volume":"107","author":"Perez","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1099\/vir.0.009639-0","article-title":"NS2\/NEP protein regulates transcription and replication of the influenza virus RNA genome","volume":"90","author":"Robb","year":"2009","journal-title":"J. Gen. Virol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"10208","DOI":"10.1021\/bi101011j","article-title":"Regulation of influenza RNA polymerase activity and the switch between replication and transcription by the concentrations of the vRNA 5\u2019 end, the cap source, and the polymerase","volume":"49","author":"Olson","year":"2010","journal-title":"Biochemistry"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Chen, K.Y., Santos Afonso, E.D., Enouf, V., Isel, C., and Naffakh, N. (2019). Influenza virus polymerase subunits co-evolve to ensure proper levels of dimerization of the heterotrimer. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1008034"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1128\/JVI.02656-12","article-title":"Identification of novel influenza A virus proteins translated from PA mRNA","volume":"87","author":"Muramoto","year":"2013","journal-title":"J. Virol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1126\/science.1222213","article-title":"An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response","volume":"337","author":"Jagger","year":"2012","journal-title":"Science"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"120109","DOI":"10.1098\/rsob.120109","article-title":"Ribosomal frameshifting used in influenza A virus expression occurs within the sequence UCC_UUU_CGU and is in the +1 direction","volume":"2","author":"Firth","year":"2012","journal-title":"Open Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"12411","DOI":"10.1128\/JVI.01677-12","article-title":"Evolutionary conservation of the PA-X open reading frame in segment 3 of influenza A virus","volume":"86","author":"Shi","year":"2012","journal-title":"J. Virol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1099\/0022-1317-73-3-575","article-title":"Degradation of cellular mRNA during influenza virus infection: Its possible role in protein synthesis shutoff","volume":"73","author":"Beloso","year":"1992","journal-title":"J. Gen. Virol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1128\/mcb.2.12.1644-1648.1982","article-title":"Inhibition of host protein synthesis and degradation of cellular mRNAs during infection by influenza and herpes simplex virus","volume":"2","author":"Inglis","year":"1982","journal-title":"Mol. Cell. Biol."},{"key":"ref_91","first-page":"2198","article-title":"Metabolism and expression of RNA polymerase II transcripts in influenza virus-infected cells","volume":"4","author":"Katze","year":"1984","journal-title":"Mol. Cell. Biol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Bercovich-Kinori, A., Tai, J., Gelbart, I.A., Shitrit, A., Ben-Moshe, S., Drori, Y., Itzkovitz, S., Mandelboim, M., and Stern-Ginossar, N. (2016). A systematic view on influenza induced host shutoff. Elife, 5.","DOI":"10.7554\/eLife.18311"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/S1097-2765(04)00091-7","article-title":"Lytic KSHV infection inhibits host gene expression by accelerating global mRNA turnover","volume":"13","author":"Glaunsinger","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1073\/pnas.84.7.1926","article-title":"Herpes simplex virus-infected cells contain a function(s) that destabilizes both host and viral mRNAs","volume":"84","author":"Kwong","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1006\/viro.1998.9508","article-title":"Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems","volume":"252","author":"Egorov","year":"1998","journal-title":"Virology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.coviro.2015.01.007","article-title":"Functions of the influenza A virus NS1 protein in antiviral defense","volume":"12","author":"Krug","year":"2015","journal-title":"Curr. Opin. Virol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1099\/vir.0.2008\/004606-0","article-title":"The multifunctional NS1 protein of influenza A viruses","volume":"89","author":"Hale","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/S1097-2765(00)80099-4","article-title":"Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3\u2019end formation of cellular pre-mRNAs","volume":"1","author":"Nemeroff","year":"1998","journal-title":"Mol. Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"10452","DOI":"10.1073\/pnas.0403212101","article-title":"The evolution of H5N1 influenza viruses in ducks in southern China","volume":"101","author":"Chen","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"13093","DOI":"10.1073\/pnas.0805213105","article-title":"Structural basis for suppression of a host antiviral response by influenza A virus","volume":"105","author":"Das","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"6909","DOI":"10.1128\/JVI.00081-10","article-title":"Inefficient control of host gene expression by the 2009 pandemic H1N1 influenza A virus NS1 protein","volume":"84","author":"Hale","year":"2010","journal-title":"J. Virol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Chaimayo, C., Dunagan, M., Hayashi, T., Santoso, N., and Takimoto, T. (2018). Specificity and functional interplay between influenza virus PA-X and NS1 shutoff activity. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007465"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3108","DOI":"10.1128\/JVI.02826-12","article-title":"Identification of the N-terminal domain of the influenza virus PA responsible for the suppression of host protein synthesis","volume":"87","author":"Desmet","year":"2013","journal-title":"J. Virol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"7131","DOI":"10.1128\/JVI.00954-16","article-title":"Critical Role of the PA-X C-Terminal Domain of Influenza A Virus in Its Subcellular Localization and Shutoff Activity","volume":"90","author":"Hayashi","year":"2016","journal-title":"J. Virol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"432","DOI":"10.3389\/fmicb.2019.00432","article-title":"Identification of Amino Acid Residues in Influenza A Virus PA-X That Contribute to Enhanced Shutoff Activity","volume":"10","author":"Oishi","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"6442","DOI":"10.1128\/JVI.00319-15","article-title":"Influenza A Virus Protein PA-X Contributes to Viral Growth and Suppression of the Host Antiviral and Immune Responses","volume":"89","author":"Hayashi","year":"2015","journal-title":"J. Virol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Khaperskyy, D.A., Schmaling, S., Larkins-Ford, J., McCormick, C., and Gaglia, M.M. (2016). Selective degradation of host RNA polymerase II transcripts by influenza A virus PA-X host shutoff protein. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005427"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"8661","DOI":"10.1128\/JVI.01132-15","article-title":"Mapping of a Region of the PA-X Protein of Influenza A Virus That Is Important for Its Shutoff Activity","volume":"89","author":"Oishi","year":"2015","journal-title":"J. Virol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1099\/vir.0.000143","article-title":"Twenty amino acids at the C-terminus of PA-X are associated with increased influenza A virus replication and pathogenicity","volume":"96","author":"Gao","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.virol.2018.01.004","article-title":"Identification of novel amino acid residues of influenza virus PA-X that are important for PA-X shutoff activity by using yeast","volume":"516","author":"Oishi","year":"2018","journal-title":"Virology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.celrep.2019.03.063","article-title":"The Influenza A Virus Endoribonuclease PA-X Usurps Host mRNA Processing Machinery to Limit Host Gene Expression","volume":"27","author":"Gaucherand","year":"2019","journal-title":"Cell Rep."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Kowalinski, E., Zubieta, C., Wolkerstorfer, A., Szolar, O.H., Ruigrok, R.W., and Cusack, S. (2012). Structural analysis of specific metal chelating inhibitor binding to the endonuclease domain of influenza pH1N1 (2009) polymerase. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002831"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.celrep.2018.06.078","article-title":"N-Terminal Acetylation by NatB Is Required for the Shutoff Activity of Influenza A Virus PA-X","volume":"24","author":"Oishi","year":"2018","journal-title":"Cell Rep."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"4555","DOI":"10.1093\/jxb\/ery241","article-title":"N-terminal acetylation: An essential protein modification emerges as an important regulator of stress responses","volume":"69","author":"Linster","year":"2018","journal-title":"J. Exp. Bot."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"12449","DOI":"10.1073\/pnas.1210303109","article-title":"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB","volume":"109","author":"Lasa","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2736","DOI":"10.1128\/JVI.02336-06","article-title":"Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice","volume":"81","author":"Szretter","year":"2007","journal-title":"J. Virol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"8262","DOI":"10.1038\/srep08262","article-title":"The contribution of PA-X to the virulence of pandemic 2009 H1N1 and highly pathogenic H5N1 avian influenza viruses","volume":"5","author":"Gao","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"4126","DOI":"10.1128\/JVI.02132-14","article-title":"PA-X decreases the pathogenicity of highly pathogenic H5N1 influenza A virus in avian species by inhibiting virus replication and host response","volume":"89","author":"Hu","year":"2015","journal-title":"J. Virol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.vetmic.2017.05.004","article-title":"PA-X protein decreases replication and pathogenicity of swine influenza virus in cultured cells and mouse models","volume":"205","author":"Gong","year":"2017","journal-title":"Vet. Microbiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.femsre.2004.12.003","article-title":"Role of apoptosis and cytokines in influenza virus morbidity","volume":"29","author":"Brydon","year":"2005","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1099\/jgv.0.000232","article-title":"PA-X is a virulence factor in avian H9N2 influenza virus","volume":"96","author":"Gao","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1056\/NEJMoa1716197","article-title":"Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents","volume":"379","author":"Hayden","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1097\/QCO.0000000000000532","article-title":"Influenza virus polymerase inhibitors in clinical development","volume":"32","author":"Hayden","year":"2019","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Jones, J.C., Kumar, G., Barman, S., Najera, I., White, S.W., Webby, R.J., and Govorkova, E.A. (2018). Identification of the I38T PA Substitution as a Resistance Marker for Next-Generation Influenza Virus Endonuclease Inhibitors. mBio, 9.","DOI":"10.1128\/mBio.00430-18"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"9633","DOI":"10.1038\/s41598-018-27890-4","article-title":"Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil","volume":"8","author":"Omoto","year":"2018","journal-title":"Sci. Rep."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/4\/365\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:11:46Z","timestamp":1760173906000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/4\/365"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,26]]},"references-count":125,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["v12040365"],"URL":"https:\/\/doi.org\/10.3390\/v12040365","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,26]]}}}