Phosphoproteomics to characterize host response during influenza a virus infection of human macrophages

Molecular and Cellular Proteomics

Volumn 15, Issue 10, 2016, Pages 3203-3219

  Soderholm, Sandra ^a   Kainov, Denis E ^b   Ohman, Tiina ^c   Denisova, Oxana V ^c   Schepens, Bert ^g   Kulesskiy, Evgeny ^e   Imanishi, Susumu Y ^f,h   Corthals, Garry ^c,i   Hintsanen, Petteri ^c   Aittokallio, Tero ^e   Saelens, Xavier ^f   Matikainen, Sampsa ^d   Nyman, Tuula A ^a,g  

^a UNIVERSITY OF HELSINKI   (Finland)

^b FINNISH INSTITUTE OF OCCUPATIONAL HEALTH   (Finland)

^c UNIVERSITY OF HELSINKI   (Finland)

^d DEPARTMENT OF PLANT SYSTEMS BIOLOGY   (Belgium)

^e GHENT UNIVERSITY   (Belgium)

^f UNIVERSITY OF TURKU   (Finland)

^g UNIVERSITY OF OSLO   (Norway)

^h MEIJO UNIVERSITY   (Japan)

ⁱ UNIVERSITY OF AMSTERDAM   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

BETA1 INTERFERON; CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE KINASE; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYCLIN DEPENDENT KINASE; CYCLIN DEPENDENT KINASE 1; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE INHIBITOR; DEAD BOX PROTEIN; DNA DIRECTED RNA POLYMERASE; FORKHEAD TRANSCRIPTION FACTOR; GLYCOGEN SYNTHASE KINASE 3BETA; I KAPPA B ALPHA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INITIATION FACTOR; INTERFERON REGULATORY FACTOR 3; INTERLEUKIN 29; MATRIX PROTEIN 2; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE 3; NONSTRUCTURAL PROTEIN 1; NUCLEAR RECEPTOR COACTIVATOR; NUCLEOPORIN; NUCLEOPROTEIN; PHOSPHOPEPTIDE; PHOSPHOPROTEIN; PROTEOME; SORTING NEXIN; TRIM22 PROTEIN; TRIM25 PROTEIN; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; ARTICLE; CARBOXY TERMINAL SEQUENCE; CELL DEATH; CELL DIVISION; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOKINE RELEASE; CYTOLYSIS; ENDOCYTOSIS; ENZYME ACTIVITY; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; GENE CONTROL; HUMAN; HUMAN CELL; IMMUNE RESPONSE; IN VITRO STUDY; INFLUENZA A; INTRACELLULAR SIGNALING; MACROPHAGE; MASS SPECTROMETRY; MITOCHONDRIAL MEMBRANE POTENTIAL; MOUSE; NONHUMAN; PHOSPHOPROTEOMICS; PRIMARY CELL; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA TRANSPORT; SIGNAL TRANSDUCTION; UBIQUITINATION; UPREGULATION; VIRUS CELL INTERACTION; VIRUS REPLICATION; WESTERN BLOTTING; ANIMAL; BIOLOGY; GENE EXPRESSION REGULATION; HOST PATHOGEN INTERACTION; INFLUENZA; INFLUENZA A VIRUS; METABOLISM; PATHOGENICITY; PROCEDURES; PROTEOMICS; VIROLOGY;

ANIMALS; COMPUTATIONAL BIOLOGY; CYCLIN-DEPENDENT KINASES; GENE EXPRESSION REGULATION; HOST-PATHOGEN INTERACTIONS; HUMANS; INFLUENZA A VIRUS; INFLUENZA, HUMAN; MACROPHAGES; MICE; PHOSPHOPROTEINS; PROTEOMICS; SIGNAL TRANSDUCTION;

EID: 84991276375     PISSN: 15359476     EISSN: 15359484     Source Type: Journal    
DOI: 10.1074/mcp.M116.057984     Document Type: Article

References (89)

1. Flannery, B., Clippard, J., Zimmerman, R. K., Nowalk, M. P., Jackson, M. L., Jackson, L. A., Monto, A. S., Petrie, J. G., McLean, H. Q., Belongia, E. A., Gaglani, M., Berman, L., Foust, A., Sessions, W., Thaker, S. N., Spencer, S., Fry, A. M., and Centers for Disease Control and Prevention.(2015) Early estimates of seasonal influenza vaccine effectiveness-united states, january 2015. MMWR Morb. Mortal. Wkly. Rep. 64, 10-15
2. Spanakis, N., Pitiriga, V., Gennimata, V., and Tsakris, A. (2014) A review of neuraminidase inhibitor susceptibility in influenza strains. Expert Rev. Anti Infect. Ther. 12, 1325-1336
3. Hurt, A. C. (2014) The epidemiology and spread of drug resistant human influenza viruses. Curr. Opin. Virol. 8C, 22-29
4. Greco, T. M., Diner, B. A., and Cristea, I. M. (2014) The impact of mass Spectrometry-Based proteomics on fundamental discoveries in virology. Ann. Rev. Virol. 1, 581-604
5. Meissner, F., and Mann, M. (2014) Quantitative shotgun proteomics: Con-siderations for a high-quality workflow in immunology. Nat. Immunol. 15, 112-117
6. Liu, Z., Wang, Y., and Xue, Y. (2013) Phosphoproteomics-based network medicine. FEBS J. 280, 5696-5704
7. Wojcechowskyj, J. A., Didigu, C. A., Lee, J. Y., Parrish, N. F., Sinha, R., Hahn, B. H., Bushman, F. D., Jensen, S. T., Seeholzer, S. H., and Doms, R. W. (2013) Quantitative phosphoproteomics reveals extensive cellular reprogramming during HIV-1 entry. Cell. Host Microbe 13, 613-623
8. Stahl, J. A., Chavan, S. S., Sifford, J. M., MacLeod, V., Voth, D. E., Edmondson, R. D., and Forrest, J. C. (2013) Phosphoproteomic analyses reveal signaling pathways that facilitate lytic gammaherpesvirus replication. PLoS Pathog. 9, e1003583
9. Luo, R., Fang, L., Jin, H., Wang, D., An, K., Xu, N., Chen, H., and Xiao, S. (2014) Label-free quantitative phosphoproteomic analysis reveals differentially regulated proteins and pathway in PRRSV-infected pulmonary alveolar macrophages. J. Proteome Res. 13, 1270-1280
10. Popova, T. G., Turell, M. J., Espina, V., Kehn-Hall, K., Kidd, J., Narayanan, A., Liotta, L., Petricoin EF3rd, Kashanchi, F., Bailey, C., and Popov, S. G. (2010) Reverse-phase phosphoproteome analysis of signaling pathways induced by rift valley fever virus in human small airway epithelial cells. PLoS ONE 5, e13805
11. Ohman, T., Soderholm, S., Paidikondala, M., Lietzen, N., Matikainen, S., and Nyman, T. A. (2015) Phosphoproteome characterization reveals that sendai virus infection activates mTOR signaling in human epithelial cells. Proteomics 15, 2087-2097
12. Oberstein, A., Perlman, D. H., Shenk, T., and Terry, L. J. (2015) Human cytomegalovirus pUL97 kinase induces global changes in the infected cell phosphoproteome. Proteomics 15, 2006-2022
13. Medzhitov, R. (2008) Origin and physiological roles of inflammation. Nature 454, 428-435
14. Hashimoto, Y., Moki, T., Takizawa, T., Shiratsuchi, A., and Nakanishi, Y. (2007) Evidence for phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and macrophages in mice. J. Immunol. 178, 2448-2457
15. Lietzen, N., Ohman, T., Rintahaka, J., Julkunen, I., Aittokallio, T., Ma-tikainen, S., and Nyman, T. A. (2011) Quantitative subcellular proteome and secretome profiling of influenza A virus-infected human primary macrophages. PLoS Pathog. 7, e1001340
16. Pirhonen, J., Sareneva, T., Kurimoto, M., Julkunen, I., and Matikainen, S. (1999) Virus infection activates IL-1 beta and IL-18 production in human macrophages by a caspase-1-dependent pathway. J. Immunol. 162, 7322-7329
17. Francis, T., and Magill, T. P. (1935) Immunological studies with the virus of influenza. J. Exp. Med. 62, 505-516
18. Ohman, T., Soderholm, S., Hintsanen, P., Valimaki, E., Lietzen, N., MacK-intosh, C., Aittokallio, T., Matikainen, S., and Nyman, T. A. (2014) Phos-phoproteomics combined with quantitative 14-3-3-affinity capture identifies SIRT1 and RAI as novel regulators of cytosolic dsRNA recognition pathway. Mol. Cell. Proteomics 13, 2604-2617
19. Kauko, O., Laajala, T. D., Jumppanen, M., Hintsanen, P., Suni, V., Haapa-niemi, P., Corthals, G., Aittokallio, T., Westermarck, J., and Imanishi, S. Y. (2015) Label-free quantitative phosphoproteomics with novel pair-wise abundance normalization reveals synergistic RAS and CIP2A signaling. Sci. Rep. 5, 13099
20. Vizcaino, J. A., Deutsch, E. W., Wang, R., Csordas, A., Reisinger, F., Rios, D., Dianes, J. A., Sun, Z., Farrah, T., Bandeira, N., Binz, P. A., Xenarios, I., Eisenacher, M., Mayer, G., Gatto, L., Campos, A., Chalkley, R. J., Kraus, H. J., Albar, J. P., Martinez-Bartolome, S., Apweiler, R., Omenn, G. S., Martens, L., Jones, A. R., and Hermjakob, H. (2014) Proteome-Xchange provides globally coordinated proteomics data submission and dissemination. Nat. Biotechnol. 32, 223-226
21. Taus, T., Kocher, T., Pichler, P., Paschke, C., Schmidt, A., Henrich, C., and Mechtler, K. (2011) Universal and confident phosphorylation site local-ization using phosphoRS. J. Proteome Res. 10, 5354-5362
22. Soderholm, S., Hintsanen, P., Ohman, T., Aittokallio, T., and Nyman, T. A. (2014) PhosFox: A bioinformatics tool for peptide-level processing of LC-MS/MS-based phosphoproteomic data. Proteome Sci. 12, 36-5956-12-36. eCollection 2014
23. Breuer, K., Foroushani, A. K., Laird, M. R., Chen, C., Sribnaia, A., Lo, R., Winsor, G. L., Hancock, R. E., Brinkman, F. S., and Lynn, D. J. (2013) InnateDB: Systems biology of innate immunity and beyond-recent updates and continuing curation. Nucleic Acids Res. 41, D1228-D33
24. Horn, H., Schoof, E. M., Kim, J., Robin, X., Miller, M. L., Diella, F., Palma, A., Cesareni, G., Jensen, L. J., and Linding, R. (2014) KinomeXplorer: An integrated platform for kinome biology studies. Nat. Methods 11, 603-604
25. Lachmann, A., and Ma'ayan, A. (2009) KEA: Kinase enrichment analysis. Bioinformatics 25, 684-686
26. Denisova, O. V., Soderholm, S., Virtanen, S., Von Schantz, C., Bychkov, D., Vashchinkina, E., Desloovere, J., Tynell, J., Ikonen, N., Theisen, L. L., Nyman, T. A., Matikainen, S., Kallioniemi, O., Julkunen, I., Muller, C. P., Saelens, X., Verkhusha, V. V., and Kainov, D. E. (2014) Akt inhibitor MK2206 prevents influenza pH1N1 virus infection in vitro. Antimicrob. Agents Chemother. 58, 3689-3696
27. Osterlund, P., Veckman, V., Siren, J., Klucher, K. M., Hiscott, J., Matikainen, S., and Julkunen, I. (2005) Gene expression and antiviral activity of alpha/beta interferons and interleukin-29 in virus-infected human mye-loid dendritic cells. J. Virol. 79, 9608-9617
28. Ohman, T., Lietzen, N., Valimaki, E., Melchjorsen, J., Matikainen, S., and Nyman, T. A. (2010) Cytosolic RNA recognition pathway activates 14-3-3 protein mediated signaling and caspase-dependent disruption of cytokeratin network in human keratinocytes. J. Proteome Res. 9, 1549-1564
29. Sato, M., Suemori, H., Hata, N., Asagiri, M., Ogasawara, K., Nakao, K., Nakaya, T., Katsuki, M., Noguchi, S., Tanaka, N., and Taniguchi, T. (2000) Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity 13, 539-548
30. Weber, A., Wasiliew, P., and Kracht, M. (2010) Interleukin-1 (IL-1) pathway. Sci. Signal. 3, cm1
31. Heylbroeck, C., Balachandran, S., Servant, M. J., DeLuca, C., Barber, G. N., Lin, R., and Hiscott, J. (2000) The IRF-3 transcription factor mediates sendai virus-induced apoptosis. J. Virol. 74, 3781-3792
32. Chattopadhyay, S., and Sen, G. C. (2010) IRF-3 and bax: A deadly affair. Cell. Cycle 9, 2479-2480
33. Hornbeck, P. V., Kornhauser, J. M., Tkachev, S., Zhang, B., Skrzypek, E., Murray, B., Latham, V., and Sullivan, M. (2012) PhosphoSitePlus: A comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res. 40, D261-D70
34. Gnad, F., Gunawardena, J., and Mann, M. (2011) PHOSIDA 2011: The posttranslational modification database. Nucleic Acids Res. 39, D253-D60
35. 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
36. 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
37. Hale, B. G., Randall, R. E., Ortin, J., and Jackson, D. (2008) The multifunc-tional NS1 protein of influenza A viruses. J. Gen. Virol. 89, 2359-2376
38. Stasakova, J., Ferko, B., Kittel, C., Sereinig, S., Romanova, J., Katinger, H., and Egorov, A. (2005) Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1beta and 18. J. Gen. Virol. 86, 185-195
39. Cheong, W. C., Kang, H. R., Yoon, H., Kang, S. J., Ting, J. P., and Song, M. J. (2015) Influenza A virus NS1 protein inhibits the NLRP3 inflam-masome. PLoS ONE 10, e0126456
40. Anastasina, M., Schepens, B., Soderholm, S., Nyman, T. A., Matikainen, S., Saksela, K., Saelens, X., and Kainov, D. E. (2015) The C-terminus of NS1 protein of influenza A/WSN/1933(H1N1) virus modulates antiviral responses in infected human macrophages and mice. J. Gen. Virol. 96, 2086-2091
41. Okumura, N., Ikeda, M., Satoh, S., Dansako, H., Sugiyama, M., Mizokami, M., and Kato, N. (2015) Negative regulation of hepatitis B virus replication by forkhead box protein A in human hepatoma cells. FEBS Lett. 589, 1112-1118
42. Di Pietro, A., Kajaste-Rudnitski, A., Oteiza, A., Nicora, L, Towers, G. J., Mechti, N., and Vicenzi, E. (2013) TRIM22 inhibits influenza A virus infection by targeting the viral nucleoprotein for degradation. J. Virol. 87, 4523-4533
43. Gack, M. U., Albrecht, R. A., Urano, T., Inn, K. S., Huang, I. C, Carnero, E., Farzan, M., Inoue, S., Jung, J. U., and Garcia-Sastre, A. (2009) Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell. Host Microbe 5, 439-449
44. Ohman, T., Rintahaka, J., Kalkkinen, N., Matikainen, S., and Nyman, T. A. (2009) Actin and RIG-I/MAVS signaling components translocate to mitochondria upon influenza A virus infection of human primary macro phages. J. Immunol. 182, 5682-5692
45. Galvan Morales, M. A., Cabello Gutierrez, C, Mejia Nepomuceno, F., Valle Peralta, L, Valencia Maqueda, E., and Manjarrez Zavala, M. E. (2014) Parainfluenza virus type 1 induces epithelial IL-8 production via p38-MAPK signalling. J. Immunol. Res. 515984, 2014
46. Zaborowska, J., Baumli, S., Laitem, C, O'Reilly, D., Thomas, P. H., O'Hare, P., and Murphy, S. (2014) Herpes simplex virus 1 (HSV-1) ICP22 protein directly interacts with cyclin-dependent kinase (CDK)9 to inhibit RNA polymerase II transcription elongation. PLoS ONE 9, e107654
47. Haolong, C, Du, N., Hongchao, T., Yang, Y., Wei, Z., Hua, Z., Wenliang, Z., Lei, S., and Po, T. (2013) Enterovirus 71 VP1 activates calmodulin-de-pendent protein kinase II and results in the rearrangement of vimentin in human astrocyte cells. PLoS ONE 8, e73900
48. Gee, K., Angel, J. B., Mishra, S., Blahoianu, M. A., and Kumar, A. (2007) IL-10 regulation by HIV-tat in primary human monocytic cells: Involvement of calmodulin/calmodulin-dependent protein kinase-activated p38 MAPK and sp-1 and CREB-1 transcription factors. J. Immunol. 178, 798-807
49. Barnitz, R. A., Wan, F., Tripuraneni, V., Bolton, D. L, and Lenardo, M. J. (2010) Protein kinase A phosphorylation activates vpr-induced cell cycle arrest during human immunodeficiency virus type 1 infection. J. Virol. 84, 6410-6424
50. Li, J., Yu, M., Zheng, W., and Liu, W. (2015) Nucleocytoplasmic shuttling of influenza A virus proteins. Viruses 7, 2668-2682
51. Fujioka, Y., Tsuda, M., Nanbo, A., Hattori, T., Sasaki, J., Sasaki, T., Mi-yazaki, T., and Ohba, Y. (2013) A ca(2+)-dependent signalling circuit regulates influenza A virus internalization and infection. Nat. Commun. 4, 2763
52. Lakdawala, S. S., Wu, Y., Wawrzusin, P., Kabat, J., Broadbent, A. J., Lamirande, E. W., Fodor, E., Altan-Bonnet, N., Shroff, H., and Subbarao, K. (2014) Influenza a virus assembly intermediates fuse in the cytoplasm. PLoS Pathog. 10, e1003971
53. Konig, R., Stertz, S., Zhou, Y., Inoue, A., Hoffmann, H. H., Bhattacharyya, S., Alamares, J. G., Tscherne, D. M., Ortigoza, M. B., Liang, Y., Gao, Q., Andrews, S. E., Bandyopadhyay, S., De Jesus, P., Tu, B. P., Pache, L., Shih, C, Orth, A., Bonamy, G., Miraglia, L., Ideker, T., Garcia-Sastre, A., Young, J. A., Palese, P., Shaw, M. L., and Chanda, S. K. (2010) Human host factors required for influenza virus replication. Nature 463, 813-817
54. Khan, K. A., Do, F., Marineau, A., Doyon, P., Clement, J. F., Woodgett, J. R., Doble, B. W., and Servant, M. J. (2015) Fine-tuning of the RIG-I-like Receptor/Interferon regulatory factor 3-dependent antiviral innate immune response by the glycogen synthase kinase 3/beta-catenin pathway. Mol. Cell. Biol. 35, 3029-3043
55. Ludwig, S., Planz, O., Pleschka, S., and Wolff, T. (2003) Influenza-virus-induced signaling cascades: Targets for antiviral therapy? Trends Mol. Med. 9, 46-52
56. 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-depend-ent intracellular pH change required for fusion. Cell. Microbiol. 13, 587-601
57. Nacken, W., Anhlan, D., Hrincius, E. R., Mostafa, A., Wolff, T., Sadewasser, A., Pleschka, S., Ehrhardt, C., and Ludwig, S. (2014) Activation of c-jun N-terminal kinase upon influenza A virus (IAV) infection is independent of pathogen-related receptors but dependent on amino acid sequence variations of IAV NS1. J. Virol. 88, 8843-8852
58. Borgeling, 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 re-sponses and protects mice from lethal H5N1 infection. J. Biol. Chem. 289, 13-27
59. Berger, K. L., Cooper, J. D., Heaton, N. S., Yoon, R., Oakland, T. E., Jordan, T. X., Mateu, G., Grakoui, A., and Randall, G. (2009) Roles for endocytic trafficking and phosphatidylinositol 4-kinase III alpha in hepatitis C virus replication. Proc. Natl. Acad. Sci. U.S.A. 106, 7577-7582
60. Jamaluddin, M., Tian, B., Boldogh, I., Garofalo, R. P., and Brasier, A. R. (2009) Respiratory syncytial virus infection induces a reactive oxygen species-MSK1-phospho-ser-276 RelA pathway required for cytokine ex-pression. J. Virol. 83, 10605-10615
61. Karlas, A., Machuy, N., Shin, Y., Pleissner, K. P., Artarini, A., Heuer, D., Becker, D., Khalil, H., Ogilvie, L. A., Hess, S., Maurer, A. P., Muller, E., Wolff, T., Rudel, T., and Meyer, T. F. (2010) Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463, 818-822
62. Hattlmann, C. J., Kelly, J. N., and Barr, S. D. (2012) TRIM22: A diverse and dynamic antiviral protein. Mol. Biol. Int.:153415, 2012
63. Gack, M. U., Shin, Y. C., Joo, C. H., Urano, T., Liang, C., Sun, L., Takeuchi, O., Akira, S., Chen, Z., Inoue, S., and Jung, J. U. (2007) TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916-920
64. Zhang, H., Wang, D., Zhong, H., Luo, R., Shang, M., Liu, D., Chen, H., Fang, L., and Xiao, S. (2015) Ubiquitin-specific protease 15 negatively regulates virus-induced type I interferon signaling via catalytically-dependent and-independent mechanisms. Sci. Rep. 5, 11220
65. Zhong, H., Wang, D., Fang, L., Zhang, H., Luo, R., Shang, M., Ouyang, C., Ouyang, H., Chen, H., and Xiao, S. (2013) Ubiquitin-specific proteases 25 negatively regulates virus-induced type I interferon signaling. PLoS ONE 8, e80976
66. Jacobs, J. L., and Coyne, C. B. (2013) Mechanisms of MAVS regulation at the mitochondrial membrane. J. Mol. Biol. 425, 5009-5019
67. Liu, S., Cai, X., Wu, J., Cong, Q., Chen, X., Li, T., Du, F., Ren, J., Wu, Y. T., Grishin, N. V., and Chen, Z. J. (2015) Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Sci-ence 347, aaa2630
68. Hu, J., Rho, H. S., Newman, R. H., Zhang, J., Zhu, H., and Qian, J. (2014) PhosphoNetworks: A database for human phosphorylation networks. Bioinformatics 30, 141-142
69. Berro, R., Pedati, C., Kehn-Hall, K., Wu, W., Klase, Z., Even, Y., Geneviere, A. M., Ammosova, T., Nekhai, S., and Kashanchi, F. (2008) CDK13, a new potential human immunodeficiency virus type 1 inhibitory factor regulat-ing viral mRNA splicing. J. Virol. 82, 7155-7166
70. Bakre, A., Andersen, L. E., Meliopoulos, V., Coleman, K., Yan, X., Brooks, P., Crabtree, J., Tompkins, S. M., and Tripp, R. A. (2013) Identification of host kinase genes required for influenza virus replication and the regulatory role of MicroRNAs. PLoS ONE 8, e66796
71. Munakata, T., Inada, M., Tokunaga, Y., Wakita, T., Kohara, M., and No-moto, A. (2014) Suppression of hepatitis C virus replication by cyclin-dependent kinase inhibitors. Antiviral Res. 108, 79-87
72. Kapasi, A. J., Clark, C. L., Tran, K., and Spector, D. H. (2009) Recruitment of cdk9 to the immediate-early viral transcriptosomes during human cytomegalovirus infection requires efficient binding to cyclin T1, a threshold level of IE2 86, and active transcription. J. Virol. 83, 5904-5917
73. Kapasi, A. J., and Spector, D. H. (2008) Inhibition of the cyclin-dependent kinases at the beginning of human cytomegalovirus infection specifically alters the levels and localization of the RNA polymerase II carboxyl-terminal domain kinases cdk9 and cdk7 at the viral transcriptosome. J. Virol. 82, 394-407
74. Hutterer, C., Eickhoff, J., Milbradt, J., Korn, K., Zeittrager, I., Bahsi, H., Wagner, S., Zischinsky, G., Wolf, A., Degenhart, C., Unger, A., Baumann, M., Klebl, B., and Marschall, M. (2015) A novel CDK7 inhibitor of the pyrazolotriazine class exerts broad-spectrum antiviral activity at nano-molar concentrations. Antimicrob. Agents Chemother. 59, 2062-2071
75. Wang, D., de la Fuente, C., Deng, L., Wang, L., Zilberman, I., Eadie, C., Healey, M., Stein, D., Denny, T., Harrison, L. E., Meijer, L., and Kashan-chi, F. (2001) Inhibition of human immunodeficiency virus type 1 transcription by chemical cyclin-dependent kinase inhibitors. J. Virol. 75, 7266-7279
76. Pauls, E., Badia, R., Torres-Torronteras, J., Ruiz, A., Permanyer, M., Riveira-Munoz, E., Clotet, B., Marti, R., Ballana, E., and Este, J. A. (2014) Palbociclib, a selective inhibitor of cyclin-dependent kinase4/6, blocks HIV-1 reverse transcription through the control of sterile alpha motif and HD domain-containing protein-1 activity. AIDS. 28, 2213-2222
77. Breuer, D., Kotelkin, A., Ammosova, T., Kumari, N., Ivanov, A., Ilatovskiy, A. V., Beullens, M., Roane, P. R., Bollen, M., Petukhov, M. G., Kashanchi, F., and Nekhai, S. (2012) CDK2 regulates HIV-1 transcription by phos-phorylation of CDK9 on serine 90. Retrovirology 9, 94-4690-9-94
78. Kudoh, A., Daikoku, T., Sugaya, Y., Isomura, H., Fujita, M., Kiyono, T., Nishiyama, Y., and Tsurumi, T. (2004) Inhibition of S-phase cyclin-de-pendent kinase activity blocks expression of epstein-barr virus immediate-early and early genes, preventing viral lytic replication. J. Virol. 78, 104-115
79. Holcakova, J., Tomasec, P., Bugert, J. J., Wang, E. C., Wilkinson, G. W., Hrstka, R., Krystof, V., Strnad, M., and Vojtesek, B. (2010) The inhibitor of cyclin-dependent kinases, olomoucine II, exhibits potent antiviral properties. Antivir. Chem. Chemother. 20, 133-142
80. Tong, W. G., Chen, R., Plunkett, W., Siegel, D., Sinha, R., Harvey, R. D., Badros, A. Z., Popplewell, L., Coutre, S., Fox, J. A., Mahadocon, K., Chen, T., Kegley, P., Hoch, U., and Wierda, W. G. (2010) Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J. Clin. Oncol. 28, 3015-3022
81. Blachly, J. S., and Byrd, J. C. (2013) Emerging drug profile: Cyclin-depend-ent kinase inhibitors. Leuk. Lymphoma 54, 2133-2143
82. Wathelet, M. G., Lin, C. H., Parekh, B. S., Ronco, L. V., Howley, P. M., and Maniatis, T. (1998) Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo. Mol. Cell 1, 507-518
83. Rintahaka, J., Wiik, D., Kovanen, P. E., Alenius, H., and Matikainen, S. (2008) Cytosolic antiviral RNA recognition pathway activates caspases 1 and 3. J. Immunol. 180, 1749-1757
84. Nencioni, L., De Chiara, G., Sgarbanti, R., Amatore, D., Aquilano, K., Marcocci, M. E., Serafino, A., Torcia, M., Cozzolino, F., Ciriolo, M. R., Garaci, E., and Palamara, A. T. (2009) Bcl-2 expression and p38MAPK activity in cells infected with influenza A virus: Impact on virally induced apoptosis and viral replication. J. Biol. Chem. 284, 16004-16015
85. Kakkola, L., Denisova, O. V., Tynell, J., Viiliainen, J., Ysenbaert, T., Matos, R. C., Nagaraj, A., Ohman, T., Kuivanen, S., Paavilainen, H., Feng, L., Yadav, B., Julkunen, I., Vapalahti, O., Hukkanen, V., Stenman, J., Ait-tokallio, T., Verschuren, E. W., Ojala, P. M., Nyman, T., Saelens, X., Dzeyk, K., and Kainov, D. E. (2013) Anticancer compound ABT-263 accelerates apoptosis in virus-infected cells and imbalances cytokine production and lowers survival rates of infected mice. Cell. Death Dis. 4, e742
86. Li, H. X., Zhao, W., Shi, Y., Li, Y. N., Zhang, L. S., Zhang, H. Q., and Wang, D. (2015) Retinoic acid amide inhibits JAK/STAT pathway in lung cancer which leads to apoptosis. Tumour Biol. 36, 8671-8678
87. Thomas, P. G., Dash, P., Aldridge JRJr, Ellebedy, A. H., Reynolds, C., Funk, A. J., Martin, W. J., Lamkanfi, M., Webby, R. J., Boyd, K. L., Doherty, P. C., and Kanneganti, T. D. (2009) The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 30, 566-575
88. Ichinohe, T., Pang, I. K., and Iwasaki, A. (2010) Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat. Immunol. 11, 404-410
89. Nain, M., Hinder, F., Gong, J. H., Schmidt, A., Bender, A., Sprenger, H., and Gemsa, D. (1990) Tumor necrosis factor-alpha production of influenza A virus-infected macrophages and potentiating effect of lipopolysaccha-rides. J. Immunol. 145, 1921-1928