Startseite Dynamic phospho-modification of viral proteins as a crucial regulatory layer of influenza A virus replication and innate immune responses
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Dynamic phospho-modification of viral proteins as a crucial regulatory layer of influenza A virus replication and innate immune responses

  • Yvonne Boergeling ORCID logo EMAIL logo , Linda Brunotte ORCID logo und Stephan Ludwig ORCID logo
Veröffentlicht/Copyright: 2. Juni 2021

Abstract

Influenza viruses are small RNA viruses with a genome of about 13 kb. Because of this limited coding capacity, viral proteins have evolved to fulfil multiple functions in the infected cell. This implies that there must be mechanisms allowing to dynamically direct protein action to a distinct activity in a spatio-temporal manner. Furthermore, viruses exploit many cellular processes, which also have to be dynamically regulated during the viral replication cycle. Phosphorylation and dephosphorylation of proteins are fundamental for the control of many cellular responses. There is accumulating evidence that this mechanism represents a so far underestimated level of regulation in influenza virus replication. Here, we focus on the current knowledge of dynamics of phospho-modifications in influenza virus replication and show recent examples of findings underlining the crucial role of phosphorylation in viral transport processes as well as activation and counteraction of the innate immune response.


Corresponding author: Yvonne Boergeling, Institute of Virology and Interdisciplinary Center for Clinical Research (IZKF), Medical Faculty, University of Münster, Von-Esmarch-Str. 56, D-48149 Münster, Germany, E-mail:

This article is a contribution to the issue highlighting the 25th Anniversary of the Interdisciplinary Centre for Clinical Research (IZKF) Münster.


Funding source: Interdisciplinary Center for Clinical Research (IZKF)

Award Identifier / Grant number: Bör2/030/21

Award Identifier / Grant number: Bru2/015/19

Award Identifier / Grant number: Lud2/013/21

Funding source: Innovative Medical Research (IMF)

Award Identifier / Grant number: BÖ-111811

Award Identifier / Grant number: BR111905

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: BR5189/3-1

Award Identifier / Grant number: BO5122/1-1

Award Identifier / Grant number: KFO 342 P06

Award Identifier / Grant number: Lu477/23-1

Award Identifier / Grant number: SFB1009 TPB02

Funding source: Bundesministerium für Bildung und Forschung

Award Identifier / Grant number: Organo-Strat (01KX2021)

Award Identifier / Grant number: Co-IMMUNE (01KI20218)

Acknowledgements

This review is dedicated to the 90th birthday of Christoph Scholtissek, Giessen, Germany, who pioneered research on post-translational modification in influenza virus propagation.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by funding from the Deutsche Forschungsgemeinschaft (DFG), grants KFO 342 P06 (to L.B. and S.L.), BR5189/3-1 (to L.B.), BO5122/1-1 (to Y.B.), Lu477/23-1 (to S.L.) and SFB1009 TPB02 (to Y.B. and S.L.). Further financial support was provided by the BMBF for the projects Organo-Strat (01KX2021) and Co-IMMUNE (01KI20218) (to L.B. and S.L.). We are grateful for funding from the Interdisciplinary Center for Clinical Research (IZKF) granted to L.B. (Bru2/015/19), Y.B. (Bör2/030/21) and S.L. (Lud2/013/21) and the Innovative Medical Research (IMF) granted to L.B. (BR111905) and Y.B. (BÖ111811) of the Medical Faculty of the University Münster.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

References

Alsuwaidi, A.R., George, J.A., Almarzooqi, S., Hartwig, S.M., Varga, S.M., and Souid, A.-K. (2017). Sirolimus alters lung pathology and viral load following influenza A virus infection. Respir. Res. 18: 136. https://doi.org/10.1186/s12931-017-0618-6.Suche in Google Scholar PubMed PubMed Central

Ayllon, J., Garcia-Sastre, A., and Hale, B.G. (2012a). Influenza A viruses and PI3K: are there time, place and manner restrictions?. Virulence 3: 411–414. https://doi.org/10.4161/viru.20932.Suche in Google Scholar PubMed PubMed Central

Ayllon, J., Hale, B.G., and Garcia-Sastre, A. (2012b). Strain-specific contribution of NS1-activated phosphoinositide 3-kinase signaling to influenza A virus replication and virulence. J. Virol. 86: 5366–5370. https://doi.org/10.1128/jvi.06722-11.Suche in Google Scholar

Baturcam, E., Vollmer, S., Schlüter, H., Maciewicz, R.A., Kurian, N., Vaarala, O., Ludwig, S., and Cunoosamy, D.M. (2019). MEK inhibition drives anti-viral defence in RV but not RSV challenged human airway epithelial cells through AKT/p70S6K/4E-BP1 signalling. Cell Commun. Signal. 17: 78. https://doi.org/10.1186/s12964-019-0378-7.Suche in Google Scholar PubMed PubMed Central

Börgeling, Y., Schmolke, M., Viemann, D., Nordhoff, C., Roth, J., and Ludwig, S. (2014). Inhibition of p38 mitogen-activated protein kinase impairs influenza virus-induced primary and secondary host gene responses and protects mice from lethal H5N1 infection. J. Biol. Chem. 289: 13–27, https://doi.org/10.1074/jbc.m113.469239.Suche in Google Scholar

Bruchhagen, C., Jarick, M., Mewis, C., Hertlein, T., Niemann, S., Ohlsen, K., Peters, G., Planz, O., Ludwig, S., and Ehrhardt, C. (2018). Metabolic conversion of CI-1040 turns a cellular MEK-inhibitor into an antibacterial compound. Sci. Rep. 8: 9114. https://doi.org/10.1038/s41598-018-27445-7.Suche in Google Scholar PubMed PubMed Central

Brunotte, L., Flies, J., Bolte, H., Reuther, P., Vreede, F., and Schwemmle, M. (2014). The nuclear export protein of H5N1 influenza A viruses recruits Matrix 1 (M1) protein to the viral ribonucleoprotein to mediate nuclear export. J. Biol. Chem. 289: 20067–20077. https://doi.org/10.1074/jbc.m114.569178.Suche in Google Scholar

Chang, C.W., Chou, H.Y., Lin, Y.S., Huang, K.H., Chang, C.J., Hsu, T.C., and Lee, S.C. (2008). Phosphorylation at Ser473 regulates heterochromatin protein 1 binding and corepressor function of TIF1beta/KAP1. BMC Mol. Biol. 9: 61. https://doi.org/10.1186/1471-2199-9-61.Suche in Google Scholar PubMed PubMed Central

Chen, B.J., Leser, G.P., Jackson, D., and Lamb, R.A. (2008). The influenza virus M2 protein cytoplasmic tail interacts with the M1 protein and influences virus assembly at the site of virus budding. J. Virol. 82: 10059–10070. https://doi.org/10.1128/jvi.01184-08.Suche in Google Scholar

Chen, G., Liu, C.-H., Zhou, L., and Krug, R. M. (2014). Cellular DDX21 RNA helicase inhibits influenza A virus replication but is counteracted by the viral NS1 protein. Cell Host Microbe 15: 484–493, https://doi.org/10.1016/j.chom.2014.03.002.10.1016/j.chom.2014.03.002Suche in Google Scholar PubMed PubMed Central

Chenavas, S., Estrozi, L.F., Slama-Schwok, A., Delmas, B., Di Primo, C., Baudin, F., Li, X., Crepin, T., and Ruigrok, R.W. (2013). Monomeric nucleoprotein of influenza A virus. PLoS Pathog. 9: e1003275. https://doi.org/10.1371/journal.ppat.1003275.Suche in Google Scholar

Cheng, J., Tao, J., Li, B., Shi, Y., and Liu, H. (2019). The tyrosine 73 and serine 83 dephosphorylation of H1N1 swine influenza virus NS1 protein attenuates virus replication and induces high levels of β interferon. Virol. J. 16: 152. https://doi.org/10.1186/s12985-019-1255-0.Suche in Google Scholar

Cheung, C.Y., Poon, L.L., Lau, A.S., Luk, W., Lau, Y.L., Shortridge, K.F., Gordon, S., Guan, Y., and Peiris, J.S. (2002). Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?. Lancet 360: 1831–1837. https://doi.org/10.1016/s0140-6736(02)11772-7.Suche in Google Scholar

Cohen, P. (2002). The origins of protein phosphorylation. Nat. Cell Biol. 4: E127–E130. https://doi.org/10.1038/ncb0502-e127.Suche in Google Scholar PubMed

Cui, L., Mahesutihan, M., Zheng, W., Meng, L., Fan, W., Li, J., Ye, X., Liu, W., and Sun, L. (2018). CDC25B promotes influenza A virus replication by regulating the phosphorylation of nucleoprotein. Virology 525: 40–47. https://doi.org/10.1016/j.virol.2018.09.005.Suche in Google Scholar PubMed

Cui, L., Zheng, W., Li, M., Bai, X., Yang, W., Li, J., Fan, W., Gao, G.F., Sun, L., and Liu, W. (2019). Phosphorylation status of tyrosine 78 residue regulates the nuclear export and ubiquitination of influenza A virus nucleoprotein. Front. Microbiol. 10: 1816. https://doi.org/10.3389/fmicb.2019.01816.Suche in Google Scholar PubMed PubMed Central

Dawson, A.R., Wilson, G.M., Coon, J.J., and Mehle, A. (2020a). Post-translation regulation of Influenza virus replication. Annu. Rev. Virol. 7: 167–187. https://doi.org/10.1146/annurev-virology-010320-070410.Suche in Google Scholar PubMed

Dawson, A.R., Wilson, G.M., Freiberger, E.C., Mondal, A., Coon, J.J., and Mehle, A. (2020b). Phosphorylation controls RNA binding and transcription by the influenza virus polymerase. PLoS Pathog. 16: e1008841. https://doi.org/10.1371/journal.ppat.1008841.Suche in Google Scholar PubMed PubMed Central

Dou, D., Revol, R., Ostbye, H., Wang, H., and Daniels, R. (2018). Influenza A virus cell entry, replication, virion assembly and movement. Front. Immunol. 9: 1581. https://doi.org/10.3389/fimmu.2018.01581.Suche in Google Scholar PubMed PubMed Central

Ehrhardt, C., and Ludwig, S. (2009). A new player in a deadly game: influenza viruses and the PI3K/Akt signalling pathway. Cell Microbiol. 11: 863–871. https://doi.org/10.1111/j.1462-5822.2009.01309.x.Suche in Google Scholar PubMed PubMed Central

Ehrhardt, C., Marjuki, H., Wolff, T., Nurnberg, B., Planz, O., Pleschka, S., and Ludwig, S. (2006). Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence. Cell Microbiol. 8: 1336–1348. https://doi.org/10.1111/j.1462-5822.2006.00713.x.Suche in Google Scholar PubMed

Ehrhardt, C., Wolff, T., Pleschka, S., Planz, O., Beermann, W., Bode, J.G., Schmolke, M., and Ludwig, S. (2007). Influenza A virus NS1 protein activates the PI3K/Akt pathway to mediate antiapoptotic signaling responses. J. Virol. 81: 3058–3067. https://doi.org/10.1128/jvi.02082-06.Suche in Google Scholar

Eierhoff, T., Hrincius, E.R., Rescher, U., Ludwig, S., and Ehrhardt, C. (2010). The epidermal growth factor receptor (EGFR) promotes uptake of influenza A viruses (IAV) into host cells. PLoS Pathog. 6: e1001099. https://doi.org/10.1371/journal.ppat.1001099.Suche in Google Scholar PubMed PubMed Central

Flati, V., Haque, S.J., and Williams, B.R. (1996). Interferon-alpha-induced phosphorylation and activation of cytosolic phospholipase A2 is required for the formation of interferon-stimulated gene factor three. EMBO J. 15: 1566–1571. https://doi.org/10.1002/j.1460-2075.1996.tb00501.x.Suche in Google Scholar

García-Sastre, A., Egorov, A., Matassov, D., Brandt, S., Levy, D.E., Durbin, J.E., Palese, P., and Muster, T. (1998). Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252: 324–330. https://doi.org/10.1006/viro.1998.9508.Suche in Google Scholar PubMed

Goh, K.C., Haque, S.J., and Williams, B.R. (1999). p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. EMBO J. 18: 5601–5608. https://doi.org/10.1093/emboj/18.20.5601.Suche in Google Scholar PubMed PubMed Central

Haasbach, E., Hartmayer, C., and Planz, O. (2013). Combination of MEK inhibitors and oseltamivir leads to synergistic antiviral effects after influenza A virus infection in vitro. Antiviral Res. 98: 319–324. https://doi.org/10.1016/j.antiviral.2013.03.006.Suche in Google Scholar PubMed

Haasbach, E., Müller, C., Ehrhardt, C., Schreiber, A., Pleschka, S., Ludwig, S., and Planz, O. (2017). The MEK-inhibitor CI-1040 displays a broad anti-influenza virus activity in vitro and provides a prolonged treatment window compared to standard of care in vivo. Antiviral Res. 142: 178–184. https://doi.org/10.1016/j.antiviral.2017.03.024.Suche in Google Scholar PubMed

Halder, U.C., Bhowmick, R., Roy Mukherjee, T., Nayak, M.K., and Chawla-Sarkar, M. (2013). Phosphorylation drives an apoptotic protein to activate antiapoptotic genes: paradigm of influenza A matrix 1 protein function. J. Biol. Chem. 288: 14554–14568. https://doi.org/10.1074/jbc.m112.447086.Suche in Google Scholar

Hale, B.G., Jackson, D., Chen, Y.H., Lamb, R.A., and Randall, R.E. (2006). Influenza A virus NS1 protein binds p85beta and activates phosphatidylinositol-3-kinase signaling. Proc. Natl. Acad. Sci. U.S.A. 103: 14194–14199. https://doi.org/10.1073/pnas.0606109103.Suche in Google Scholar PubMed PubMed Central

Hale, B.G., Knebel, A., Botting, C.H., Galloway, C.S., Precious, B.L., Jackson, D., Elliott, R.M., and Randall, R.E. (2009). CDK/ERK-mediated phosphorylation of the human influenza A virus NS1 protein at threonine-215. Virology 383: 6–11. https://doi.org/10.1016/j.virol.2008.10.002.Suche in Google Scholar PubMed

Holsinger, L.J., Shaughnessy, M.A., Micko, A., Pinto, L.H., and Lamb, R.A. (1995). Analysis of the posttranslational modifications of the influenza virus M2 protein. J. Virol. 69: 1219. https://doi.org/10.1128/jvi.69.2.1219-1225.1995.Suche in Google Scholar PubMed PubMed Central

Hrincius, E.R., Dierkes, R., Anhlan, D., Wixler, V., Ludwig, S., and Ehrhardt, C. (2011). Phosphatidylinositol-3-kinase (PI3K) is activated by influenza virus vRNA via the pathogen pattern receptor Rig-I to promote efficient type I interferon production. Cell Microbiol. 13: 1907–1919. https://doi.org/10.1111/j.1462-5822.2011.01680.x.Suche in Google Scholar PubMed

Hrincius, E.R., Hennecke, A.-K., Gensler, L., Nordhoff, C., Anhlan, D., Vogel, P., McCullers, J.A., Ludwig, S., and Ehrhardt, C. (2012a). A single point mutation (Y89F) within the non-structural protein 1 of influenza A viruses limits epithelial cell tropism and virulence in mice. Am. J. Pathol. 180: 2361–2374. https://doi.org/10.1016/j.ajpath.2012.02.029.Suche in Google Scholar PubMed

Hrincius, E.R., Hennecke, A.K., Gensler, L., Nordhoff, C., Anhlan, D., Vogel, P., McCullers, J.A., Ludwig, S., and Ehrhardt, C. (2012b). A single point mutation (Y89F) within the non-structural protein 1 of influenza A viruses limits epithelial cell tropism and virulence in mice. Am. J. Pathol. 180: 2361–2374. https://doi.org/10.1016/j.ajpath.2012.02.029.Suche in Google Scholar

Hsiang, T.Y., Zhou, L., and Krug, R.M. (2012). Roles of the phosphorylation of specific serines and threonines in the NS1 protein of human influenza A viruses. J. Virol. 86: 10370–10376. https://doi.org/10.1128/jvi.00732-12.Suche in Google Scholar

Hu, J., Zhang, L., and Liu, X. (2020). Role of post-translational modifications in Influenza A virus life cycle and host Innate Immune response. Front. Microbiol. 11: 517461, https://doi.org/10.3389/fmicb.2020.517461.Suche in Google Scholar PubMed PubMed Central

Hubel, P., Urban, C., Bergant, V., Schneider, W.M., Knauer, B., Stukalov, A., Scaturro, P., Mann, A., Brunotte, L., Hoffmann, H.H., et al.. (2019). A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nat. Immunol. 20: 493–502. https://doi.org/10.1038/s41590-019-0323-3.Suche in Google Scholar PubMed

Humphrey, S.J., James, D.E., and Mann, M. (2015). Protein phosphorylation: a major switch mechanism for metabolic regulation. Trends Endocrinol. Metab. 26: 676–687. https://doi.org/10.1016/j.tem.2015.09.013.Suche in Google Scholar PubMed

Hutchinson, E.C., Denham, E.M., Thomas, B., Trudgian, D.C., Hester, S.S., Ridlova, G., York, A., Turrell, L., and Fodor, E. (2012). Mapping the phosphoproteome of influenza A and B viruses by mass spectrometry. PLoS Pathog. 8: e1002993. https://doi.org/10.1371/journal.ppat.1002993.Suche in Google Scholar PubMed PubMed Central

Ivashkiv, L.B. and Donlin, L.T. (2014). Regulation of type I interferon responses. Nat. Rev. Immunol. 14: 36–49. https://doi.org/10.1038/nri3581.Suche in Google Scholar PubMed PubMed Central

Jackson, D., Killip, M.J., Galloway, C.S., Russell, R.J., and Randall, R.E. (2010). Loss of function of the influenza A virus NS1 protein promotes apoptosis but this is not due to a failure to activate phosphatidylinositol 3-kinase (PI3K). Virology 396: 94–105. https://doi.org/10.1016/j.virol.2009.10.004.Suche in Google Scholar PubMed

Jiang, Y., Chen, C., Li, Z., Guo, W., Gegner, J.A., Lin, S., and Han, J. (1996). Characterization of the structure and function of a new mitogen-activated protein kinase (p38β). J. Biol. Chem. 271: 17920–17926. https://doi.org/10.1074/jbc.271.30.17920.Suche in Google Scholar PubMed

Kathum, O.A., Schräder, T., Anhlan, D., Nordhoff, C., Liedmann, S., Pande, A., Mellmann, A., Ehrhardt, C., Wixler, V., and Ludwig, S. (2016). Phosphorylation of influenza A virus NS1 protein at threonine 49 suppresses its interferon antagonistic activity. Cell Microbiol. 18: 784–791. https://doi.org/10.1111/cmi.12559.Suche in Google Scholar PubMed PubMed Central

Kistner, O., Müller, H., Becht, H., and Scholtissek, C. (1985). Phosphopeptide fingerprints of nucleoproteins of various influenza A virus strains grown in different host cells. J. Gen. Virol. 66: 465–472. https://doi.org/10.1099/0022-1317-66-3-465.Suche in Google Scholar PubMed

Kistner, O., Müller, K., and Scholtissek, C. (1989). Differential phosphorylation of the nucleoprotein of influenza A viruses. J. Gen. Virol. 70: 2421–2431. https://doi.org/10.1099/0022-1317-70-9-2421.Suche in Google Scholar PubMed

Klemm, C., Boergeling, Y., Ludwig, S., and Ehrhardt, C. (2018). Immunomodulatory nonstructural proteins of influenza A viruses. Trends Microbiol. 26: 624–636. https://doi.org/10.1016/j.tim.2017.12.006.Suche in Google Scholar PubMed

Krischuns, T., Gunl, F., Henschel, L., Binder, M., Willemsen, J., Schloer, S., Rescher, U., Gerlt, V., Zimmer, G., Nordhoff, C., et al.. (2018). Phosphorylation of TRIM28 enhances the expression of IFN-β and proinflammatory cytokines during HPAIV Infection of human lung epithelial cells. Front. Immunol. 9: 2229. https://doi.org/10.3389/fimmu.2018.02229.Suche in Google Scholar PubMed PubMed Central

Laure, M., Hamza, H., Koch-Heier, J., Quernheim, M., Müller, C., Schreiber, A., Müller, G., Pleschka, S., Ludwig, S., and Planz, O. (2020). Antiviral efficacy against influenza virus and pharmacokinetic analysis of a novel MEK-inhibitor, ATR-002, in cell culture and in the mouse model. Antiviral Res. 178: 104806. https://doi.org/10.1016/j.antiviral.2020.104806.Suche in Google Scholar PubMed

Li, W., Wang, G., Zhang, H., Shen, Y., Dai, J., Wu, L., Zhou, J., Jiang, Z., and Li, K. (2012). Inability of NS1 protein from an H5N1 influenza virus to activate PI3K/Akt signaling pathway correlates to the enhanced virus replication upon PI3K inhibition. Vet. Res. 43: 36. https://doi.org/10.1186/1297-9716-43-36.Suche in Google Scholar PubMed PubMed Central

Li, Y., Sun, L., Zheng, W., Madina, M., Li, J., Bi, Y., Wang, H., Liu, W., and Luo, T.R. (2018). Phosphorylation and dephosphorylation of threonine 188 in nucleoprotein is crucial for the replication of influenza A virus. Virology 520: 30–38. https://doi.org/10.1016/j.virol.2018.05.002.Suche in Google Scholar

Lietzén, N., Ohman, T., Rintahaka, J., Julkunen, I., Aittokallio, T., Matikainen, S., and Nyman, T.A. (2011). Quantitative subcellular proteome and secretome profiling of influenza A virus-infected human primary macrophages. PLoS Pathog. 7: e1001340. https://doi.org/10.1371/journal.ppat.1001340.Suche in Google Scholar

Lu, X., Masic, A., Li, Y., Shin, Y., Liu, Q., and Zhou, Y. (2010). The PI3K/Akt pathway inhibits influenza A virus-induced Bax-mediated apoptosis by negatively regulating the JNK pathway via ASK1. J. Gen. Virol. 91: 1439–1449. https://doi.org/10.1099/vir.0.018465-0.Suche in Google Scholar

Ludwig, S., Hrincius, E.R., and Boergeling, Y. (2021). The two sides of the same coin-influenza virus and intracellular signal transduction. Cold Spring Harb. Perspect. Med. 11: a038513, https://doi.org/10.1101/cshperspect.a038513.Suche in Google Scholar

Ludwig, S., Pleschka, S., and Wolff, T. (1999). A fatal relationship--influenza virus interactions with the host cell. Viral Immunol. 12: 175–196. https://doi.org/10.1089/vim.1999.12.175.Suche in Google Scholar

Ludwig, S., Wolff, T., Ehrhardt, C., Wurzer, W.J., Reinhardt, J., Planz, O., and Pleschka, S. (2004). MEK inhibition impairs influenza B virus propagation without emergence of resistant variants. FEBS Lett. 561: 37–43, https://doi.org/10.1016/S0014-5793(04)00108-5.10.1016/S0014-5793(04)00108-5Suche in Google Scholar

Mahmoudian, S., Auerochs, S., Grone, M., and Marschall, M. (2009). Influenza A virus proteins PB1 and NS1 are subject to functionally important phosphorylation by protein kinase C. J. Gen. Virol. 90: 1392–1397. https://doi.org/10.1099/vir.0.009050-0.Suche in Google Scholar PubMed

Mannick, J.B., Morris, M., Hockey, H.P., Roma, G., Beibel, M., Kulmatycki, K., Watkins, M., Shavlakadze, T., Zhou, W., and Quinn, D., et al.. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10: eaaq1564, https://doi.org/10.1126/scitranslmed.aaq1564.Suche in Google Scholar PubMed

Marjuki, H., Alam, M.I., Ehrhardt, C., Wagner, R., Planz, O., Klenk, H.-D., Ludwig, S., and Pleschka, S. (2006). Membrane accumulation of influenza A virus hemag-glutinin triggers nuclear export of the viral genome via protein kinase Cα-mediated activation of ERK signaling. J. Biol. Chem. 281: 16707–16715. https://doi.org/10.1074/jbc.m510233200.Suche in Google Scholar PubMed

Marjuki, H., Gornitzky, A., Marathe, B.M., Ilyushina, N.A., Aldridge, J.R., Desai, G., Webby, R.J., and Webster, R.G. (2011). Influenza A virus-induced early activation of ERK and PI3K mediates V-ATPase-dependent intracellular pH change required for fusion. Cell Microbiol. 13: 587–601. https://doi.org/10.1111/j.1462-5822.2010.01556.x.Suche in Google Scholar PubMed PubMed Central

McCown, M.F. and Pekosz, A. (2006). Distinct domains of the influenza a virus M2 protein cytoplasmic tail mediate binding to the M1 protein and facilitate infectious virus production. J. Virol. 80: 8178–8189. https://doi.org/10.1128/jvi.00627-06.Suche in Google Scholar PubMed PubMed Central

Mecate-Zambrano, A., Sukumar, S., Seebohm, G., Ciminski, K., Schreiber, A., Anhlan, D., Greune, L., Wixler, L., Grothe, S., Stein, N.C., et al.. (2020). Discrete spatio-temporal regulation of tyrosine phosphorylation directs influenza A virus M1 protein towards its function in virion assembly. PLoS Pathog. 16: e1008775. https://doi.org/10.1371/journal.ppat.1008775.Suche in Google Scholar PubMed PubMed Central

Meineke, R., Rimmelzwaan, G.F., and Elbahesh, H. (2019). Influenza virus infections and cellular kinases. Viruses 11: 171, https://doi.org/10.3390/v11020171.Suche in Google Scholar PubMed PubMed Central

Mitzner, D., Dudek, S.E., Studtrucker, N., Anhlan, D., Mazur, I., Wissing, J., Jansch, L., Wixler, L., Bruns, K., Sharma, A., et al.. (2009). Phosphorylation of the influenza A virus protein PB1-F2 by PKC is crucial for apoptosis promoting functions in monocytes. Cell Microbiol. 11: 1502–1516. https://doi.org/10.1111/j.1462-5822.2009.01343.x.Suche in Google Scholar PubMed

Mondal, A., Dawson, A.R., Potts, G.K., Freiberger, E.C., Baker, S.F., Moser, L.A., Bernard, K.A., Coon, J.J., and Mehle, A. (2017). Influenza virus recruits host protein kinase C to control assembly and activity of its replication machinery. eLife 6: e26910, https://doi.org/10.7554/elife.26910.Suche in Google Scholar PubMed PubMed Central

Mondal, A., Potts, G.K., Dawson, A.R., Coon, J.J., and Mehle, A. (2015). Phosphorylation at the homotypic interface regulates nucleoprotein oligomerization and assembly of the influenza virus replication machinery. PLoS Pathog. 11: e1004826. https://doi.org/10.1371/journal.ppat.1004826.Suche in Google Scholar PubMed PubMed Central

Neumann, G., Hughes, M.T., and Kawaoka, Y. (2000). Influenza A virus NS2 protein mediates vRNP nuclear export through NES-independent interaction with hCRM1. EMBO J. 19: 6751–6758. https://doi.org/10.1093/emboj/19.24.6751.Suche in Google Scholar PubMed PubMed Central

Patil, A., Anhlan, D., Ferrando, V., Mecate-Zambrano, A., Mellmann, A., Wixler, V., Boergeling, Y., and Ludwig, S. (2021). Phosphorylation of influenza A virus NS1 at serine 205 mediates its viral polymerase-enhancing function. J. Virol. 95: e02369–e02320. https://doi.org/10.1128/jvi.02369-20.Suche in Google Scholar

Perales, B., Sanz-Ezquerro, J.J., Gastaminza, P., Ortega, J., Santarén, J.F., Ortín, J., and Nieto, A. (2000). The replication activity of influenza virus polymerase is linked to the capacity of the PA subunit to induce proteolysis. J. Virol. 74: 1307–1312. https://doi.org/10.1128/jvi.74.3.1307-1312.2000.Suche in Google Scholar PubMed PubMed Central

Perwitasari, O., Yan, X., O’Donnell, J., Johnson, S., and Tripp, R.A. (2015). Repurposing kinase inhibitors as antiviral agents to control influenza A virus replication. Assay Drug Dev. Technol. 13: 638–649. https://doi.org/10.1089/adt.2015.0003.drrr.Suche in Google Scholar PubMed PubMed Central

Pichlmair, A. and Reis e Sousa, C. (2007). Innate recognition of viruses. Immunity 27: 370–383. https://doi.org/10.1016/j.immuni.2007.08.012.Suche in Google Scholar

Pichlmair, A., Schulz, O., Tan, C.P., Naslund, T.I., Liljestrom, P., Weber, F., and Reis e Sousa, C. (2006). RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science 314: 997–1001. https://doi.org/10.1126/science.1132998.Suche in Google Scholar

Planz, O., Pleschka, S., and Ludwig, S. (2001). MEK-specific inhibitor U0126 blocks spread of Borna disease virus in cultured cells. J. Virol. 75: 4871–4877. https://doi.org/10.1128/jvi.75.10.4871-4877.2001.Suche in Google Scholar

Pleschka, S., Wolff, T., Ehrhardt, C., Hobom, G., Planz, O., Rapp, U.R., and Ludwig, S. (2001). Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nat. Cell Biol. 3: 301–305. https://doi.org/10.1038/35060098.Suche in Google Scholar

Preugschas, H.F., Hrincius, E.R., Mewis, C., Tran, G.V.Q., Ludwig, S., and Ehrhardt, C. (2019). Late activation of the Raf/MEK/ERK pathway is required for translocation of the respiratory syncytial virus F protein to the plasma membrane and efficient viral replication. Cell Microbiol. 21: e12955. https://doi.org/10.1111/cmi.12955.Suche in Google Scholar

Reinhardt, J., and Wolff, T. (2000). The influenza A virus M1 protein interacts with the cellular receptor of activated C kinase (RACK) 1 and can be phosphorylated by protein kinase C. Vet. Microbiol. 74: 87–100. https://doi.org/10.1016/s0378-1135(00)00169-3.Suche in Google Scholar

Reuther, P., Giese, S., Gotz, V., Riegger, D., and Schwemmle, M. (2014). Phosphorylation of highly conserved serine residues in the influenza A virus nuclear export protein NEP plays a minor role in viral growth in human cells and mice. J. Virol. 88: 7668–7673. https://doi.org/10.1128/jvi.00854-14.Suche in Google Scholar

Rosario-Ferreira, N., Preto, A.J., Melo, R., Moreira, I.S., and Brito, R.M.M. (2020). The central role of non-structural protein 1 (ns1) in influenza biology and infection. Int. J. Mol. Sci. 21: 1511, https://doi.org/10.3390/ijms21041511.Suche in Google Scholar PubMed PubMed Central

Sarkar, S.N., Peters, K.L., Elco, C.P., Sakamoto, S., Pal, S., and Sen, G.C. (2004). Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling. Nat. Struct. Mol. Biol. 11: 1060–1067. https://doi.org/10.1038/nsmb847.Suche in Google Scholar PubMed

Schmidt, N., Domingues, P., Golebiowski, F., Patzina, C., Tatham, M.H., Hay, R.T., and Hale, B.G. (2019). An influenza virus-triggered SUMO switch orchestrates co-opted endogenous retroviruses to stimulate host antiviral immunity. Proc. Natl. Acad. Sci. U.S.A. 116: 17399–17408. https://doi.org/10.1073/pnas.1907031116.Suche in Google Scholar PubMed PubMed Central

Schoggins, J.W. and Rice, C.M. (2011). Interferon-stimulated genes and their antiviral effector functions. Curr. Opin. Virol. 1: 519–525. https://doi.org/10.1016/j.coviro.2011.10.008.Suche in Google Scholar PubMed PubMed Central

Schräder, T., Dudek, S.E., Schreiber, A., Ehrhardt, C., Planz, O., and Ludwig, S. (2018). The clinically approved MEK inhibitor Trametinib efficiently blocks influenza A virus propagation and cytokine expression. Antiviral Res. 157: 80–92. https://doi.org/10.1016/j.antiviral.2018.07.006.Suche in Google Scholar PubMed

Schreiber, A., Boff, L., Anhlan, D., Krischuns, T., Brunotte, L., Schuberth, C., Wedlich-Söldner, R., Drexler, H., and Ludwig, S. (2020). Dissecting the mechanism of signaling-triggered nuclear export of newly synthesized influenza virus ribonucleoprotein complexes. Proc. Natl. Acad. Sci. U.S.A. 117: 16557–16566. https://doi.org/10.1073/pnas.2002828117.Suche in Google Scholar PubMed PubMed Central

Sempere Borau, M. and Stertz, S. (2021). Entry of influenza A virus into host cells: recent progress and remaining challenges. Curr. Opin. Virol. 48: 23–29. https://doi.org/10.1016/j.coviro.2021.03.001.Suche in Google Scholar PubMed

Shin, Y.K., Li, Y., Liu, Q., Anderson, D.H., Babiuk, L.A., and Zhou, Y. (2007a). SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K/Akt signaling pathway activation. J. Virol. 81: 12730–12739. https://doi.org/10.1128/jvi.01427-07.Suche in Google Scholar

Shin, Y.K., Liu, Q., Tikoo, S.K., Babiuk, L.A., and Zhou, Y. (2007b). Effect of the phosphatidylinositol 3-kinase/Akt pathway on influenza A virus propagation. J. Gen. Virol. 88: 942–950. https://doi.org/10.1099/vir.0.82483-0.Suche in Google Scholar PubMed

Shin, Y.K., Liu, Q., Tikoo, S.K., Babiuk, L.A., and Zhou, Y. (2007c). Influenza A virus NS1 protein activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by direct interaction with the p85 subunit of PI3K. J. Gen. Virol. 88: 13–18. https://doi.org/10.1099/vir.0.82419-0.Suche in Google Scholar PubMed

Söderholm, S., Fu, Y., Gaelings, L., Belanov, S., Yetukuri, L., Berlinkov, M., Cheltsov, A.V., Anders, S., Aittokallio, T., Nyman, T.A., et al.. (2016a). Multi-omics studies towards novel modulators of influenza A virus–host Interaction. Viruses 8: 269. https://doi.org/10.3390/v8100269.Suche in Google Scholar PubMed PubMed Central

Söderholm, S., Kainov, D.E., Öhman, T., Denisova, O.V., Schepens, B., Kulesskiy, E., Imanishi, S.Y., Corthals, G., Hintsanen, P., Aittokallio, T., et al.. (2016b). Phosphoproteomics to characterize host response during Influenza A virus Infection of human macrophages. Mol. Cell. Proteom. 15: 3203–3219. https://doi.org/10.1074/mcp.m116.057984.Suche in Google Scholar PubMed PubMed Central

Steinhauer, D.A., Wharton, S.A., Skehel, J.J., and Wiley, D.C. (1995). Studies of the membrane fusion activities of fusion peptide mutants of influenza virus hemagglutinin. J. Virol. 69: 6643–6651. https://doi.org/10.1128/jvi.69.11.6643-6651.1995.Suche in Google Scholar PubMed PubMed Central

Takeuchi, O. and Akira, S. (2009). Innate immunity to virus infection. Immunol. Rev. 227: 75–86. https://doi.org/10.1111/j.1600-065x.2008.00737.x.Suche in Google Scholar PubMed PubMed Central

Thomas, J.M., Stevens, M.P., Percy, N., and Barclay, W.S. (1998). Phosphorylation of the M2 protein of influenza A virus is not essential for virus viability. Virology 252: 54–64. https://doi.org/10.1006/viro.1998.9384.Suche in Google Scholar PubMed

Turkington, H.L., Juozapaitis, M., Tsolakos, N., Corrales-Aguilar, E., Schwemmle, M., and Hale, B.G. (2018). Unexpected functional divergence of bat Influenza virus NS1 proteins. J. Virol. 92: e02097–17, https://doi.org/10.1128/jvi.02097-17.Suche in Google Scholar

Turrell, L., Hutchinson, E.C., Vreede, F.T., and Fodor, E. (2015). Regulation of influenza A virus nucleoprotein oligomerization by phosphorylation. J. Virol. 89: 1452–1455. https://doi.org/10.1128/jvi.02332-14.Suche in Google Scholar PubMed PubMed Central

Varga, Z.T. and Palese, P. (2011). The influenza A virus protein PB1-F2: killing two birds with one stone?. Virulence 2: 542–546. https://doi.org/10.4161/viru.2.6.17812.Suche in Google Scholar PubMed PubMed Central

Wang, C.H., Chung, F.T., Lin, S.M., Huang, S.Y., Chou, C.L., Lee, K.Y., Lin, T.Y., and Kuo, H.P. (2014). Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure. Crit. Care Med. 42: 313–321. https://doi.org/10.1097/ccm.0b013e3182a2727d.Suche in Google Scholar PubMed

Wang, D., Harmon, A., Jin, J., Francis, D.H., Christ opher-Hennings, J., Nelson, E., Montelaro, R.C., and Li, F. (2010). The lack of an inherent membrane targeting signal is responsible for the failure of the matrix (M1) protein of influenza A virus to bud into virus-like particles. J. Virol. 84: 4673–4681. https://doi.org/10.1128/jvi.02306-09.Suche in Google Scholar

Wang, S., Zhao, Z., Bi, Y., Sun, L., Liu, X., and Liu, W. (2013). Tyrosine 132 phosphorylation of influenza A virus M1 protein is crucial for virus replication by controlling the nuclear import of M1. J. Virol. 87: 6182–6191. https://doi.org/10.1128/jvi.03024-12.Suche in Google Scholar

Weber-Gerlach, M., and Weber, F. (2016). To conquer the host, influenza virus is packing it in: interferon-antagonistic strategies beyond NS1. J. Virol. 90: 8389–8394. https://doi.org/10.1128/jvi.00041-16.Suche in Google Scholar

Weber, A., Dam, S., Saul, V.V., Kuznetsova, I., Müller, C., Fritz-Wolf, K., Becker, K., Linne, U., Gu, H., Stokes, M.P., et al.. (2019). Phosphoproteome analysis of cells infected with adapted and non-adapted influenza A virus reveals novel pro- and antiviral signaling networks. J. Virol. 93: e00528–e00519. https://doi.org/10.1128/jvi.00528-19.Suche in Google Scholar

Weber, M., Sediri, H., Felgenhauer, U., Binzen, I., Banfer, S., Jacob, R., Brunotte, L., Garcia-Sastre, A., Schmid-Burgk, J.L., Schmidt, T., et al.. (2015). Influenza virus adaptation PB2-627K modulates nucleocapsid inhibition by the pathogen sensor RIG-I. Cell Host Microbe 17: 309–319. https://doi.org/10.1016/j.chom.2015.01.005.Suche in Google Scholar PubMed PubMed Central

Whittaker, G., Kemler, I., and Helenius, A. (1995). Hyperphosphorylation of mutant influenza virus matrix protein, M1, causes its retention in the nucleus. J. Virol. 69: 439–445. https://doi.org/10.1128/jvi.69.1.439-445.1995.Suche in Google Scholar PubMed PubMed Central

Yanguez, E., Hunziker, A., Dobay, M.P., Yildiz, S., Schading, S., Elshina, E., Karakus, U., Gehrig, P., Grossmann, J., Dijkman, R., et al.. (2018). Phosphoproteomic-based kinase profiling early in influenza virus infection identifies GRK2 as antiviral drug target. Nat. Commun. 9: 3679. https://doi.org/10.1038/s41467-018-06119-y.Suche in Google Scholar PubMed PubMed Central

York, A., Hutchinson, E.C., and Fodor, E. (2014). Interactome analysis of the Influenza A virus transcription/replication machinery Identifies protein phosphatase 6 as a cellular factor required for efficient virus replication. J. Virol. 88: 13284–13299. https://doi.org/10.1128/jvi.01813-14.Suche in Google Scholar

Zheng, W., Cao, S., Chen, C., Li, J., Zhang, S., Jiang, J., Niu, Y., Fan, W., Li, Y., Bi, Y., et al.. (2017). Threonine 80 phosphorylation of non-structural protein 1 regulates the replication of influenza A virus by reducing the binding affinity with RIG-I. Cell Microbiol. 19: e12643. https://doi.org/10.1111/cmi.12643.Suche in Google Scholar PubMed

Zheng, W., Cui, L., Li, M., Li, Y., Fan, W., Yang, L., Li, J., Sun, L., and Liu, W. (2021). Nucleoprotein phosphorylation site (Y385) mutation confers temperature sensitivity to influenza A virus due to impaired nucleoprotein oligomerization at a lower temperature. Sci. China Life Sci. 64: 633–643. https://doi.org/10.1007/s11427-020-1727-y.Suche in Google Scholar PubMed

Zheng, W., Li, J., Wang, S., Cao, S., Jiang, J., Chen, C., Ding, C., Qin, C., Ye, X., Gao, G.F., et al.. (2015). Phosphorylation controls the nuclear-cytoplasmic shuttling of influenza A virus nucleoprotein. J. Virol. 89: 5822–5834. https://doi.org/10.1128/jvi.00015-15.Suche in Google Scholar

Received: 2021-04-27
Accepted: 2021-05-18
Published Online: 2021-06-02
Published in Print: 2021-11-25

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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