猪流感病毒感染A549细胞的亚细胞蛋白组分析

英文题名：Subcellular Proteomic Analysis of Human Lung A549Cells Infected with Swine Influenza Virus
作者：吴小鹏
论文级别：博士
学科专业名称：微生物学
中文关键词：猪流感病毒 ; A549细胞 ; 亚细胞定位 ; 亚细胞蛋白质组
英文关键词：swine influenza virus ; A549cells ; subcellular distribution ; subcellular
英文关键词：proteomics
学位年度：2013
导师：周继勇
学科代码：071005
学位授予单位：浙江大学
论文提交日期：2012-12-01
答辩委员会主席：童光志

摘要

猪流感病毒(Swine influenza virus, SIV)隶属于分节段的单股负链RNA病毒正黏病毒科,除能感染猪体外,还具有感染人类的跨种间传播能力。病毒基因组为分节段的8条单股负链RNA,编码PB1、PB2、PA、NP、HA、NA、M1、 M2、NS1及NEP(NS2)等10种以上蛋白。目前关于流感病毒跨种间感染的机制研究较少。本研究以SIV感染人肺上皮细胞A549为模型,应用亚细胞蛋白组学方法对SIV感染细胞的蛋白表达变化进行了探索。
     1、SIV编码蛋白的亚细胞定位
     采用纯化病毒、Ni2+亲和纯化的原核表达蛋白NP、NS1、M1为免疫原,免疫BALB/c小鼠、新西兰大白兔,分别获得了NP蛋白单克隆抗体分泌细胞3株、M1蛋白单克隆抗体分泌细胞6株、NS1蛋白单克隆抗体分泌细胞6株及兔抗NP、NS1、M1蛋白多克隆抗体。采用荧光双标法,以制备的抗体为工具,分析了H3N2、H1N1SIV及A/PR8/34/H1N1(PR8)感染A549细胞24小时后的病毒蛋白NP、NS1和M1的亚细胞定位及病毒蛋白之间的定位关系。结果显示,H3N2、H1N1SIV(?)口PR8的NP蛋白主要集中分布于感染细胞的核内,但胞质中也有分布。SIV的M1蛋白在感染细胞的胞核、胞质均有表达,但PR8的Ml蛋白仅呈点状分布于细胞核内。SIV的NS1蛋白主要集中分布于感染细胞的核内,PR8的NS1蛋白呈点状分布于细胞核和细胞质。共定位分析显示,仅在H3N2、H1N1SIV感染细胞的核内发现NS1与NP的共定位关系。这些数据说明,两个不同亚型SIV的NP蛋白与PR8的NP蛋白亚细胞分布相同,但Ml和NS1蛋白的亚细胞分布存在差异。
     2、SIV感染细胞的胞质/胞核亚细胞蛋白质组分析
     以人肺上皮细胞A549感染猪流感病毒H3N2为感染模型,采用2-DE结合MS研究方法分析细胞感染后24小时的细胞质、细胞核亚细胞蛋白质组表达变化动态。MALDI-TOF/TOF质谱分析结果表明,胞质、胞核组分共有56个差异蛋白点(对应43种蛋白)被鉴定成功(蛋白分数大于67,p<0.05)。其中细胞质组分中对应19个上调蛋白点和15个下调蛋白点,细胞核组分中包含14个上调点和8个下调点。差异蛋白的生物功能学分析表明,SIV感染主要涉及到细胞死亡、压力应答、脂类代谢、信号转导及RAN转录和修饰方面。蛋白相互作用网络(IPA)分析表明,H3N2SIV感染主要激活NF-κB-IFN通路。同时通过对比H1N1SIV感染,利用免疫印迹(WB)和免疫荧光(IFA)验证了差异蛋白的变化规律,发现细胞蛋白WARS、IFI35、HSPB1、NMI、GNB1、GNB2等在病毒感染后有表达上调及入核的表现。免疫共沉淀分析显示NS1与hnRNP C2存在相互作用关系。siRNA干扰和瞬时过表达分析显示,与SIV H1N1感染细胞相比,WARS蛋白对SIV H3N2的M1、NP蛋白的合成量及病毒载量有明显影响。
     3、SIV感染细胞的线粒体蛋白组学分析
     线粒体作为真核生物细胞内最重要的一种亚细胞器,参与了细胞凋亡、能量代谢、应激反应及免疫应答等许多方面。为了分析H3N2亚型猪流感病毒感染A549细胞后线粒体的应答反应,本研究采用2-DE结合MS鉴定方法,分析了SIV H3N2感染A549细胞后24小时的线粒体蛋白组变化。2-DE凝胶的比较分析表明,感染前后线粒体蛋白共有29个蛋白点发生了差异表达,包括上调蛋白点16个,下调蛋白点13个。MALDI-TOF/TOF质谱成功鉴定26个差异蛋白点(蛋白分数大于67,p≤0.05),对应12种上调蛋白,11种下调蛋白。差异蛋白的生物学功能分析表明,H3N2病毒感染涉及细胞形态、免疫应答及信号转导蛋白的表达变化。差异表达蛋白的network网络和pathway通路分析结果表明,氧化磷酸化通路(Oxidative phosphorylation)、整联蛋白信号通路(1ntegrin signaling)是线粒体应答细胞感染的主要通路。实时荧光定量RT-PCR对SIV H3N2感染后24h的16个细胞差异表达蛋白的转录本分析表明,RNA加工及蛋白表达类基因、细胞死亡相关基因均是上调表现；细胞间信号转导类基因以上调为主;细胞蛋白组装类基因以下调为主；能量合成类基因的变化不大。
     综合以上信息,发现干扰素诱导表达蛋白Mx1,热休克蛋白等在三组分中均有明显上调,WARS在胞质、胞核组分中上调,hnRNP H家族蛋白在细胞核中上调,而在线粒体中下调。因此,本研究揭示的病毒感染后亚细胞蛋白质组信息为进一步开展SIV跨种间感染的分子致病机制奠定了基础。
Swine influenza virus (SIV), belongs to the family Orthomyxoviridae, contains eight negative-stranded RNA genomic segments encoding more than ten viral proteins. The virus can infect pigs in vitro, but also has the ability to infect humans and other cross-species infection. To date, the biological functions of viral proteins have been well characterized, but few studies on the mechanism of cross-species infection of swine influenza virus. In this study, swine influenza virus infection of human lung epithelial cell line A549was used as a infection model, the application of the method of subcellular proteomics protein expression in SIV-infected cells were explored.
     Subcellular distribution of SIV viral proteins
     In current research, we cloned viral NP, M1and NS1genes into prokaryotic expression vector, then purified the recombinant protein (rNP, rM1and rNS1) with nickel-column chromatography. Polyclonal antibodies and six monoclonal antibodies (mAbs) against M1, six mAbs against NS1and one mAb against NP were produce using purified rM1, rNS1and rNP respectively. At the same time we purified SIV virion through sucrose density gradient centrifugation and obtained two mAbs against NP with purified virion immunized BALB/c mice.
     Using a dual fluorescent staining, we analyzed the sub-cellular localization relations between viral proteins NP, NS1and M1in A549cells after SIV H3N2, SIV H1N1and A/PR8/34/H1N1(PR8) infected24hours, respectively. The results showed that the distribution of NP is similar in SIV and PR8infection, localized in both nucleus and cytoplasm. After SIV infection, M1has a significant expression in nuclear and cytoplasmic fraction, but in the PR8-infected cells, M1mainly localized in the nuclear with punctated distribution. NS1are mainly concentrated in the nucleus after SIV infection but in the PR8-infected cells, it showed a punctate distribution both in nuclear and cytoplasm. In the the SIV H3N2or SIV H1N1infected cells, NS1can co-localized with NP in the nucleus, while this colonialization was not observed in PR8-infected cell. The colonialization between M1and NP, M1and NS1was not obvious in all three viruses-infected cells.
     Cytoplasmic and nuclear proteomic changes in A549infected with SIV
     To uncover human cellular dynamics response to SIV, the sub-cellular proteome profiles were analyzed utilizing two-dimensional gel electrophoresis (2-DE) followed by MALDI-TOF/TOF identification. Comparative analysis of multiple2-DE gels and then by Mass spectrometry revealed that in cytoplasmic proteomes identified34altered cellular proteins, including19up-regulated proteins and15down-regulated proteins; in nuclear proteomes identified22altered cellular proteins, including14up-regulated proteins and8down-regulated proteins. Cellular function analysis of differential expression proteins mainly involved in several aspects of cell death, stress response, lipid metabolism, cell signaling, and RNA Post-Transcriptional Modification. Ingenuity Pathway Analysis (IPA) revealed that proteins that changed in response to infection could be grouped into NF-kappa B and Interferon pathways. By using immunoblotting (WB), We found the WARS, IFI35, HSPB1, GNB1can translocate into nucleus after H3N2or H1N1infection. Using immunofluorescence assay (IFA) analysis, we found WARS, NMI, hnRNP U and hnRNP C1/C2can take subcellular location or change expressed levels upon SIV infection. Using co-immunoprecipitation (CoIP) analysis, We further confirmed the interaction between SIV H3N2NS1and hnRNP C2. Not only knockdown but also transient over express of WARS can cause the protein levels of M1and NP reduced, which specific to H3N2infection but not H1N1infection.
     Mitochondrion proteomic changes in A549infected with SIV
     Mitochondrion is one of the most important subcellular organelles in eukaryotic cells, and mainly involved in apoptosis, energy metabolism, stress response and immune response in many ways. In order to investigate the mitochondrial response to swine influenza virus infection in A549cells, especially the changes profile of the mitochondrial proteome. In this study, the mitochondrion was isolated from SIV-infected and mock-infected A549cells at24h post infection time, and comparative mitochondrion proteomes were analyzed with two-dimensional gel electrophoresis (2-DE) followed by MALDI-TOF/TOF protein identification.2-DE gel analysis showed29protein spots were differentially expressed (silver staining intensity greater than or equal to2) after virus infection. Including16up-regulated expressed protein spots and13down-regulated expressed protein spots. Mass spectrometry successfully identified26protein spots (corresponding to23altered cellular proteins), including12up-regulated proteins and11down regulated proteins. a total of26differentially expressed proteins were identified successfully. The cellular function analysis of differential expressed proteins mainly involved in cell mediated immune response, cell morphology, and cell-to-cell signal transduction. IPA network and pathway analysis of differentially expressed proteins reveal that oxidative phosphorylation pathway and integrin signaling pathway are the main pathway of mitochondrion protein response to SIV infection. In addition to validate the2-DE data, real-time RT-PCR analysis of16differentially expressed proteins corresponding to five cellular functions. The result showed that a class of RNA and protein processing genes and cell death genes were up-regulated; cell-to-cell signal transduction genes were mainly up-regulated but protein assembly genes were mainly down-regulated; The energy synthetic genes showed no changes after virus infection.
     Based on the above information, we found that the expression of interferon-inducible protein Mx1, heat shock proteins significantly increased in three component, WARS up-regulated in both of cytoplasm and nucleus. hnRNP H family proteins are increased in the nucleus proteomes, while in mitochondrial are down-regulated. Collectively this work provide useful subcellular proteomics informations about human host cell responding to SIV virus infection.

引文

1. Medina RA, Garcia-Sastre A.2011. Influenza A viruses:new research developments. Nat Rev Microbiol 9:590-603
    2. Taubenberger JK, Kash JC.2010. Influenza virus evolution, host adaptation, and pandemic formation. Cell Host Microbe 7:440-51
    3. Boulo S, Akarsu H, Ruigrok RW, Baudin F.2007. Nuclear traffic of influenza virus proteins and ribonucleoprotein complexes. Virus Res 124:12-21
    4. Gabriel G, Herwig A, Klenk HD.2008. Interaction of polymerase subunit PB2 and NP with importin alphal is a determinant of host range of influenza A virus. PLoS Pathog 4:e11
    5. Ocana-Macchi M, Ricklin ME, Python S, Monika GA, Stech J, Stech O, Summerfield A.2012. Avian influenza A virus PB2 promotes interferon type I inducing properties of a swine strain in porcine dendritic cells. Virology 427:1-9
    6. Hudjetz B, Gabriel G.2012. Human-like PB2 627K influenza virus polymerase activity is regulated by importin-alphal and -alpha7. PLoS Pathog 8:e1002488
    7. Poole EL, Medcalf L, Elton D, Digard P.2007. Evidence that the C-terminal PB2-binding region of the influenza A virus PB1 protein is a discrete alpha-helical domain. FEBS Lett 581: 5300-6
    8. Biswas SK, Nayak DP.1994. Mutational analysis of the conserved motifs of influenza A virus polymerase basic protein 1. J Virol 68:1819-26
    9. Ghanem A, Mayer D, Chase G, Tegge W, Frank R, Kochs G, Garcia-Sastre A, Schwemmle M. 2007. Peptide-mediated interference with influenza A virus polymerase. J Virol 81:7801-4
    10. Xu C, Hu WB, Xu K, He YX, Wang TY, Chen Z, Li TX, Liu JH, Buchy P, Sun B.2012. Amino acids 473V and 598P of PB1 from an avian-origin influenza A virus contribute to polymerase activity, especially in mammalian cells. J Gen Virol 93:531-40
    11. Kosik I, Krejnusova I, Praznovska M, Polakova K, Russ G.2012. A DNA vaccine expressing PB1 protein of influenza A virus protects mice against virus infection. Arch Virol
    12. Sanz-Ezquerro JJ, Fernandez Santaren J, Sierra T, Aragon T, Ortega J, Ortin J, Smith GL, Nieto A.1998. The PA influenza virus polymerase subunit is a phosphorylated protein. J Gen Virol 79(Pt3):471-8
    13. Perales B, Sanz-Ezquerro JJ, Gastaminza P, Ortega J, Santaren JF, Ortin J, Nieto A.2000. The replication activity of influenza virus polymerase is linked to the capacity of the PA subunit to induce proteolysis. J Virol 74:1307-12
    14. Liang Y, Danzy S, Dao LD, Parslow TG.2012. Mutational analyses of the influenza A virus polymerase subunit PA reveal distinct functions related and unrelated to RNA polymerase activity. PLoS One 7:e29485
    15. Mehle A, Dugan VG, Taubenberger JK, Doudna JA.2012. Reassortment and mutation of the avian influenza virus polymerase PA subunit overcome species barriers. J Virol 86:1750-7
    16. Nayak DP, Jabbar MA.1989. Structural domains and organizational conformation involved in the sorting and transport of influenza virus transmembrane proteins. Annu Rev Microbiol 43: 465-501
    17. Fouchier RA, Munster V, Wallensten A, Bestebroer TM, Herfst S, Smith D, Rimmelzwaan GF, Olsen B, Osterhaus AD.2005. Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. J Virol 79:2814-22
    18. Bosch FX, Garten W, Klenk HD, Rott R.1981. Proteolytic cleavage of influenza virus hemagglutinins:primary structure of the connecting peptide between HA1 and HA2 determines proteolytic cleavability and pathogenicity of Avian influenza viruses. Virology 113: 725-35
    19. Wang W, Suguitan AL, Jr., Zengel J, Chen Z, Jin H.2012. Generation of recombinant pandemic H1N1 influenza virus with the HA cleavable by bromelain and identification of the residues influencing HA bromelain cleavage. Vaccine 30:872-8
    20. Hoper D, Kalthoff D, Hoffmann B, Beer M.2012. Highly pathogenic avian influenza virus subtype H5N1 escaping neutralization:more than HA variation. J Virol 86:1394-404
    21. Ng AK, Zhang H, Tan K, Li Z, Liu JH, Chan PK, Li SM, Chan WY, Au SW, Joachimiak A, Walz T, Wang JH, Shaw PC.2008. Structure of the influenza virus A H5N1 nucleoprotein: implications for RNA binding, oligomerization, and vaccine design. FASEB J 22:3638-47
    22. Kobayashi M, Toyoda T, Adyshev DM, Azuma Y, Ishihama A.1994. Molecular dissection of influenza virus nucleoprotein:deletion mapping of the RNA binding domain.J Virol 68: 8433-6
    23. Portela A, Digard P.2002. The influenza virus nucleoprotein:a multifunctional RNA-binding protein pivotal to virus replication. J Gen Virol 83:723-34
    24. Ma W, Liu Q, Bawa B, Qiao C, Qi W, Shen H, Chen Y, Ma J, Li X, Webby RJ, Garcia-Sastre A, Richt JA.2012. The NA and M genes of the 2009 pandemic influenza H1N1 virus functionally cooperate to facilitate efficient replication and transmissibility in pigs. J Gen Virol
    25. Wang S, Li H, Chen Y, Wei H, Gao GF, Liu H, Huang S, Chen JL.2012. Transport of influenza A virus neuraminidase (NA) to host cell surface is regulated by ARHGAP21 and Cdc42. JBiol Chem
    26. Arzt S, Petit I, Burmeister WP, Ruigrok RW, Baudin F.2004. Structure of a knockout mutant of influenza virus M1 protein that has altered activities in membrane binding, oligomerisation and binding to NEP (NS2). Virus Res 99:115-9
    27. Itoh M, Hotta H.1997. [Structure, function and regulation of expression of influenza virus matrix M1 protein]. Nihon Rinsho 55:2581-6
    28. Das SC, Watanabe S, Hatta M, Noda T, Neumann G, Ozawa M, Kawaoka Y.2012. The highly conserved arginine residues at positions 76 through 78 of influenza A virus matrix protein M1 play an important role in viral replication by affecting the intracellular localization of M1. J Virol 86:1522-30
    29. Liu X, Zhao Z, Xu C, Sun L, Chen J, Zhang L, Liu W.2012. Cyclophilin A Restricts Influenza A Virus Replication through Degradation of the M1 Protein. PLoS One 7:e31063
    30. Pinto LH, Lamb RA.2007. Controlling influenza virus replication by inhibiting its proton channel. Mol Biosyst 3:18-23
    31. Iwatsuki-Horimoto K, Horimoto T, Noda T, Kiso M, Maeda J, Watanabe S, Muramoto Y, Fujii K, Kawaoka Y.2006. The cytoplasmic tail of the influenza A virus M2 protein plays a role in viral assembly. J Virol 80:5233-40
    32. Esghaei M, Monavari SH, Tavassoti-Kheiri M, Shamsi-Shahrabadi M, Heydarchi B, Farahmand B, Saleh M, Fotouhi F.2012. Expression of the influenza M2 protein in three different eukaryotic cell lines. J Virol Methods 179:161-5
    33. Krug RM, Etkind PR.1973. Cytoplasmic and nuclear virus-specific proteins in influenza virus-infected MDCK cells. Virology 56:334-48
    34. Nemeroff ME, Qian XY, Krug RM.1995. The influenza virus NS1 protein forms multimers in vitro and in vivo. Virology 212:422-8
    35. Newby CM, Sabin L, Pekosz A.2007. The RNA binding domain of influenza A virus NS 1 protein affects secretion of tumor necrosis factor alpha, interleukin-6, and interferon in primary murine tracheal epithelial cells. J Virol 81:9469-80
    36. Privalsky ML, Penhoet EE.1981. The structure and synthesis of influenza virus phosphoproteins. J Biol Chem 256:5368-76
    37. Hale BG, Randall RE, Ortin J, Jackson D.2008. The multifunctional NS1 protein of influenza A viruses. J Gen Virol 89:2359-76
    38. Inglis SC, Barrett T, Brown CM, Almond JW.1979. The smallest genome RNA segment of influenza virus contains two genes that may overlap. Proc Natl Acad Sci U S A 76:3790-4
    39. O'Neill RE, Jaskunas R, Blobel G, Palese P, Moroianu J.1995. Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import. JBiol Chem 270:22701-4
    40. Paragas J, Talon J, O'Neill RE, Anderson DK, Garcia-Sastre A, Palese P.2001. Influenza B and C virus NEP (NS2) proteins possess nuclear export activities. J Virol 75:7375-83
    41. Odagiri T, Tobita K.1990. Mutation in NS2, a nonstructural protein of influenza A virus, extragenically causes aberrant replication and expression of the PA gene and leads to generation of defective interfering particles. Proc Natl Acad Sci USA 87:5988-92
    42. Zohari S, Gyarmati P, Thoren P, Czifra G, Brojer C, Belak S, Berg M.2008. Genetic characterization of the NS gene indicates co-circulation of two sub-lineages of highly pathogenic avian influenza virus of H5N1 subtype in Northern Europe in 2006. Virus Genes 36:117-25
    43. Zamarin D, Garcia-Sastre A, Xiao X, Wang R, Palese P.2005. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog 1:e4
    44. Gibbs JS, Malide D, Hornung F, Bennink JR, Yewdell JW.2003. The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function. J Virol 77:7214-24
    45. Wise HM, Foeglein A, Sun J, Dalton RM, Patel S, Howard W, Anderson EC, Barclay WS, Digard P.2009. A complicated message:Identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. J Virol 83:8021-31
    46. Colman PM, Lawrence MC.2003. The structural biology of type Ⅰ viral membrane fusion. Nat Rev Mol Cell Biol 4:309-19
    47. Muller M, Katsov K, Schick M.2003. A new mechanism of model membrane fusion determined from Monte Carlo simulation. Biophys J 85:1611-23
    48. Engelhardt OG, Fodor E.2006. Functional association between viral and cellular transcription during influenza virus infection. Rev Med Virol 16:329-45
    49. Alonso-Caplen FV, Krug RM.1991. Regulation of the extent of splicing of influenza virus NS1 mRNA:role of the rates of splicing and of the nucleocytoplasmic transport of NS1 mRNA. Mol Cell Biol 11:1092-8
    50. Jensen TH, Dower K, Libri D, Rosbash M.2003. Early formation of mRNP:license for export or quality control? Mol Cell 11:1129-38
    51. Vreede FT, Jung TE, Brownlee GG.2004. Model suggesting that replication of influenza virus is regulated by stabilization of replicative intermediates. J Virol 78:9568-72
    52. Garfinkel MS, Katze MG.1993. How does influenza virus regulate gene expression at the level of mRNA translation? Let us count the ways. Gene Expr 3:109-18
    53. Lu Y, Wambach M, Katze MG, Krug RM.1995. Binding of the influenza virus NS1 protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the elF-2 translation initiation factor. Virology 214:222-8
    54. Katze MG, Tomita J, Black T, Krug RM, Safer B, Hovanessian A.1988. Influenza virus regulates protein synthesis during infection by repressing autophosphorylation and activity of the cellular 68,000-Mr protein kinase. J Virol 62:3710-7
    55. Kundu A, Avalos RT, Sanderson CM, Nayak DP.1996. Transmembrane domain of influenza virus neuraminidase, a type Ⅱ protein, possesses an apical sorting signal in polarized MDCK cells. J Virol 70:6508-15
    56. Wandinger-Ness A, Bennett MK, Antony C, Simons K.1990. Distinct transport vesicles mediate the delivery of plasma membrane proteins to the apical and basolateral domains of MDCK cells. J Cell Biol 111:987-1000
    57. Huang X, Liu T, Muller J, Levandowski RA, Ye Z.2001. Effect of influenza virus matrix protein and viral RNA on ribonucleoprotein formation and nuclear export. Virology 287: 405-16
    58. Zhao H, Ekstrom M, Garoff H.1998. The M1 and NP proteins of influenza A virus form homo-but not heterooligomeric complexes when coexpressed in BHK-21 cells. J Gen Virol 79 (Pt 10):2435-46
    59. Garcia-Sastre A, Palese P.1995. The cytoplasmic tail of the neuraminidase protein of influenza A virus does not play an important role in the packaging of this protein into viral envelopes. Virus Res 37:37-47
    60. Takeda M, Leser GP, Russell CJ, Lamb RA.2003. Influenza virus hemagglutinin concentrates in lipid raft microdomains for efficient viral fusion. Proc Nail Acad Sci U S A 100:14610-7
    61. Suzuki T, Tsukimoto M, Kobayashi M, Yamada A, Kawaoka Y, Webster RG, Suzuki Y.1994. Sialoglycoproteins that bind influenza A virus and resist viral neuraminidase in different animal sera. J Gen Virol 75 (Pt 7):1769-74
    62. Ito T, Suzuki Y, Takada A, Kawamoto A, Otsuki K, Masuda H, Yamada M, Suzuki T, Kida H, Kawaoka Y.1997. Differences in sialic acid-galactose linkages in the chicken egg amnion and allantois influence human influenza virus receptor specificity and variant selection. J Virol 71: 3357-62
    63. Ito T, Kawaoka Y.2000. Host-range barrier of influenza A viruses. Vet Microbiol 74:71-5
    64. Suzuki Y, Ito T, Suzuki T, Holland RE, Jr., Chambers TM, Kiso M, Ishida H, Kawaoka Y. 2000. Sialic acid species as a determinant of the host range of influenza A viruses. J Virol 74: 11825-31
    65. Suzuki Y, Kato H, Naeve CW, Webster RG.1989. Single-amino-acid substitution in an antigenic site of influenza virus hemagglutinin can alter the specificity of binding to cell membrane-associated gangliosides. J Virol 63:4298-302
    66. Hatta M, Gao P, Halfmann P, Kawaoka Y.2001. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293:1840-2
    67. Stevens J, Corper AL, Basler CF, Taubenberger JK, Palese P, Wilson IA.2004. Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science 303: 1866-70
    68. Brown EG, Liu H, Kit LC, Baird S, Nesrallah M.2001. Pattern of mutation in the genome of influenza A virus on adaptation to increased virulence in the mouse lung:identification of functional themes. Proc Natl Acad Sci USA 98:6883-8
    69. Hughes MT, McGregor M, Suzuki T, Suzuki Y, Kawaoka Y.2001. Adaptation of influenza A viruses to cells expressing low levels of sialic acid leads to loss of neuraminidase activity. J Virol 75:3766-70
    70. Kobasa D, Kodihalli S, Luo M, Castrucci MR, Donatelli I, Suzuki Y, Suzuki T, Kawaoka Y. 1999. Amino acid residues contributing to the substrate specificity of the influenza A virus neuraminidase. J Virol 73:6743-51
    71. Baum LG, Paulson JC.1991. The N2 neuraminidase of human influenza virus has acquired a substrate specificity complementary to the hemagglutinin receptor specificity. Virology 180: 10-5
    72. Lamblin G, Aubert JP, Perini JM, Klein A, Porchet N, Degand P, Roussel P.1992. Human respiratory mucins. Eur Respir J 5:247-56
    73. Xu G, Suzuki T, Maejima Y, Mizoguchi T, Tsuchiya M, Kiso M, Hasegawa A, Suzuki Y.1995. Sialidase of swine influenza A viruses:variation of the recognition specificities for sialyl linkages and for the molecular species of sialic acid with the year of isolation. Glycoconj J 12: 156-61
    74. Guo CT, Takahashi N, Yagi H, Kato K, Takahashi T, Yi SQ, Chen Y, Ito T, Otsuki K, Kida H, Kawaoka Y, Hidari KI, Miyamoto D, Suzuki T, Suzuki Y.2007. The quail and chicken intestine have sialyl-galactose sugar chains responsible for the binding of influenza A viruses to human type receptors. Glycobiology 17:713-24
    75. Weingartl HM, Albrecht RA, Lager KM, Babiuk S, Marszal P, Neufeld J, Embury-Hyatt C, Lekcharoensuk P, Tumpey TM, Garcia-Sastre A, Richt JA.2009. Experimental infection of pigs with the human 1918 pandemic influenza virus. J Virol 83:4287-96
    76. Yu H, Zhang PC, Zhou YJ, Li GX, Pan J, Yan LP, Shi XX, Liu HL, Tong GZ.2009. Isolation and genetic characterization of avian-like H1N1 and novel ressortant H1N2 influenza viruses from pigs in China. Biochem Biophys Res Commun 386:278-83
    77. Neumann G, Noda T, Kawaoka Y.2009. Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 459:931-9
    78. Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, Ma SK, Cheung CL, Raghwani J, Bhatt S, Peiris JS, Guan Y, Rambaut A.2009. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 459:1122-5
    79. Zhou J, Sun W, Wang J, Guo J, Yin W, Wu N, Li L, Yan Y, Liao M, Huang Y, Luo K, Jiang X, Chen H.2009. Characterization of the H5N1 highly pathogenic avian influenza virus derived from wild pikas in China. J Virol 83:8957-64
    80. Saito T, Lim W, Suzuki T, Suzuki Y, Kida H, Nishimura SI, Tashiro M.2001. Characterization of a human H9N2 influenza virus isolated in Hong Kong. Vaccine 20:125-33
    81. Guillot L, Le Goffic R, Bloch S, Escriou N, Akira S, Chignard M, Si-Tahar M.2005. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus. J Biol Chem 280:5571-80
    82. Fujita T, Onoguchi K, Onomoto K, Hirai R, Yoneyama M.2007. Triggering antiviral response by RIG-I-related RNA helicases. Biochimie 89:754-60
    83. Ishikawa E, Nakazawa M, Yoshinari M, Minami M.2005. Role of tumor necrosis factor-related apoptosis-inducing ligand in immune response to influenza virus infection in mice. J Virol 79:7658-63
    84. Ji WT, Liu HJ.2008. PI3K-Akt signaling and viral infection. Recent Pat Biotechnol 2:218-26
    85. Sieczkarski SB, Brown HA, Whittaker GR.2003. Role of protein kinase C betaⅡ in influenza virus entry via late endosomes. J Virol 77:460-9
    86. Olschlager V, Pleschka S, Fischer T, Rziha HJ, Wurzer W, Stitz L, Rapp UR, Ludwig S, Planz O.2004. Lung-specific expression of active Raf kinase results in increased mortality of influenza A virus-infected mice. Oncogene 23:6639-46
    87. Ghosh S, Karin M.2002. Missing pieces in the NF-kappaB puzzle. Cell 109 Suppl:S81-96
    88. Maruoka S, Hashimoto S, Gon Y, Nishitoh H, Takeshita I, Asai Y, Mizumura K, Shimizu K, Ichijo H, Horie T.2003. ASK1 regulates influenza virus infection-induced apoptotic cell death. Biochem Biophys Res Commun 307:870-6
    89. Le Goffic R, Pothlichet J, Vitour D, Fujita T, Meurs E, Chignard M, Si-Tahar M.2007. Cutting Edge:Influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells. J Immunol 178:3368-72
    90. Wathelet MG, Lin CH, Parekh BS, Ronco LV, Howley PM, Maniatis T.1998. Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo. Mol Cell 1:507-18
    91. Agalioti T, Lomvardas S, Parekh B, Yie J, Maniatis T, Thanos D.2000. Ordered recruitment of chromatin modifying and general transcription factors to the IFN-beta promoter. Cell 103: 667-78
    92. Kumar N, Xin ZT, Liang Y, Ly H.2008. NF-kappaB signaling differentially regulates influenza virus RNA synthesis. J Virol 82:9880-9
    93. Ellis AE.2001. Innate host defense mechanisms of fish against viruses and bacteria. Dev Comp Immunol 25:827-39
    94. Accola MA, Huang B, Al Masri A, McNiven MA.2002. The antiviral dynamin family member, MxA, tubulates lipids and localizes to the smooth endoplasmic reticulum. J Biol Chem 277:21829-35
    95. Kochs G, Janzen C, Hohenberg H, Haller O.2002. Antivirally active MxA protein sequesters La Crosse virus nucleocapsid protein into perinuclear complexes. Proc Natl Acad Sci USA 99: 3153-8
    96. Szuchet S, Plachetzki DC, Karialukas R.2002. Oligodendrocytes express an alpha/beta-interferon-susceptible Mx gene:molecular characterization of the encoded protein. Glior 37:183-9
    97. Garcia MA, Meurs EF, Esteban M.2007. The dsRNA protein kinase PKR:virus and cell control. Biochimie 89:799-811
    98. Takizawa T, Ohashi K, Nakanishi Y.1996. Possible involvement of double-stranded RNA-activated protein kinase in cell death by influenza virus infection. J Virol 70:8128-32
    99. Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM.2005. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A 102:10200-5
    100. Lu G, Reinert JT, Pitha-Rowe I, Okumura A, Kellum M, Knobeloch KP, Hassel B, Pitha PM. 2006. ISG15 enhances the innate antiviral response by inhibition of IRF-3 degradation. Cell Mol Biol (Noisy-le-grand) 52:29-41
    101. Lenschow DJ, Lai C, Frias-Staheli N, Giannakopoulos NV, Lutz A, Wolff T, Osiak A, Levine B, Schmidt RE, Garcia-Sastre A, Leib DA, Pekosz A, Knobeloch KP, Horak I, Virgin HWt. 2007. IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc Natl Acad Sci USA 104:1371-6
    102. Zhao C, Hsiang TY, Kuo RL, Krug RM.2010. ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells. Proc Natl Acad Sci U S A 107:2253-8
    103. Hovanessian AG, Justesen J.2007. The human 2'-5'oligoadenylate synthetase family:unique interferon-inducible enzymes catalyzing 2'-5'instead of 3'-5'phosphodiester bond formation. Biochimie 89:779-88
    104. George CX, Samuel CE.1999. Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. Proc Natl Acad Sci USA 96:4621-6
    105. Jung E, Heller M, Sanchez JC, Hochstrasser DF.2000. Proteomics meets cell biology:the establishment of subcellular proteomes. Electrophoresis 21:3369-77
    106. Andersen JS, Lam YW, Leung AK, Ong SE, Lyon CE, Lamond AI, Mann M.2005. Nucleolar proteome dynamics. Nature 433:77-83
    107. Gorski S, Misteli T.2005. Systems biology in the cell nucleus. J Cell Sci 118:4083-92
    108. Bhoj VG, Chen ZJ.2009. Ubiquitylation in innate and adaptive immunity. Nature 458:430-7
    109. Kim JY, Anderson ED, Huynh W, Dey A, Ozato K.2011. Proteomic survey of ubiquitin-linked nuclear proteins in interferon-stimulated macrophages. J Interferon Cytokine Res 31:619-28
    110. Pewsey E, Bruce C, Tonge P, Evans C, Ow SY, Georgiou AS, Wright PC, Andrews PW, Fazeli A.2010. Nuclear proteome dynamics in differentiating embryonic carcinoma (NTERA-2) cells. J Proteome Res 9:3412-26
    111. Chan EY, Qian WJ, Diamond DL, Liu T, Gritsenko MA, Monroe ME, Camp DG,2nd, Smith RD, Katze MG.2007. Quantitative analysis of human immunodeficiency virus type 1-infected CD4+ cell proteome:dysregulated cell cycle progression and nuclear transport coincide with robust virus production. J Virol 81:7571-83
    112. Lee BJ, Kwon SJ, Kim SK, Kim KJ, Park CJ, Kim YJ, Park OK, Paek KH.2006. Functional study of hot pepper 26S proteasome subunit RPN7 induced by Tobacco mosaic virus from nuclear proteome analysis. Biochem Biophys Res Commun 351:405-11
    113. Cao JY, Mansouri S, Frappier L.2012. Changes in the nasopharyngeal carcinoma nuclear proteome induced by the EBNA1 protein of Epstein-Barr virus reveal potential roles for EBNA1 in metastasis and oxidative stress responses. J Virol 86:382-94
    114. Bowick GC, Spratt HM, Hogg AE, Endsley JJ, Wiktorowicz JE, Kurosky A, Luxon BA, Gorenstein DG, Herzog NK.2009. Analysis of the differential host cell nuclear proteome induced by attenuated and virulent hemorrhagic arenavirus infection. J Virol 83:687-700
    115. Dundr M, Misteli T.2002. Nucleolomics:an inventory of the nucleolus. Mol Cell 9:5-7
    116. Olson MO, Dundr M, Szebeni A.2000. The nucleolus:an old factory with unexpected capabilities. Trends Cell Biol 10:189-96
    117. Bernardi R, Pandolfi PP.2003. The nucleolus:at the stem of immortality. Nat Med 9:24-5
    118. Ginisty H, Sicard H, Roger B, Bouvet P.1999. Structure and functions of nucleolin. J Cell Sci 112 (Pt 6):761-72
    119. Tsai RY, McKay RD.2002. A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev 16:2991-3003
    120. Hinsby AM, Kiemer L, Karlberg EO, Lage K, Fausboll A, Juncker AS, Andersen JS, Mann M, Brunak S.2006. A wiring of the human nucleolus. Mol Cell 22:285-95
    121. Scherl A, Coute Y, Deon C, Calle A, Kindbeiter K, Sanchez JC, Greco A, Hochstrasser D, Diaz JJ.2002. Functional proteomic analysis of human nucleolus. Mol Biol Cell 13:4100-9
    122. Pyper JM, Clements JE, Zink MC.1998. The nucleolus is the site of Borna disease virus RNA transcription and replication. J Virol 72:7697-702
    123. Michienzi A, Cagnon L, Bahner I, Rossi JJ.2000. Ribozyme-mediated inhibition of HIV 1 suggests nucleolar trafficking of HIV-1 RNA. Proc Nail Acad Sci U S A 97:8955-60
    124. Hiscox JA.2002. The nucleolus--a gateway to viral infection? Arch Virol 147:1077-89
    125. Matthews DA.2001. Adenovirus protein V induces redistribution of nucleolin and B23 from nucleolus to cytoplasm. J Virol 75:1031-8
    126. Okuwaki M, Iwamatsu A, Tsujimoto M, Nagata K.2001. Identification of nucleophosmin/B23, an acidic nucleolar protein, as a stimulatory factor for in vitro replication of adenovirus DNA complexed with viral basic core proteins. J Mol Biol 311:41-55
    127. Waggoner S, Sarnow P.1998. Viral ribonucleoprotein complex formation and nucleolar-cytoplasmic relocalization of nucleolin in poliovirus-infected cells.J Virol 72: 6699-709
    128. Hiscox JA, Wurm T, Wilson L, Britton P, Cavanagh D, Brooks G.2001. The coronavirus infectious bronchitis virus nucleoprotein localizes to the nucleolus. J Virol 75:506-12
    129. Emmott E, Wise H, Loucaides EM, Matthews DA, Digard P, Hiscox J A.2010. Quantitative proteomics using SILAC coupled to LC-MS/MS reveals changes in the nucleolar proteome in influenza A virus-infected cells. J Proteome Res 9:5335-45
    130. Emmott E, Rodgers MA, Macdonald A, McCrory S,Ajuh P, Hiscox JA.2010. Quantitative proteomics using stable isotope labeling with amino acids in cell culture reveals changes in the cytoplasmic, nuclear, and nucleolar proteomes in Vero cells infected with the coronavirus infectious bronchitis virus. Mol Cell Proteomics 9:1920-36
    131. Hiscox JA.2007. RNA viruses:hijacking the dynamic nucleolus. Nat Rev Microbiol 5:119-27
    132. Eckert A, Keil U, Marques CA, Bonert A, Frey C, Schussel K, Muller WE.2003. Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease. Biochem Pharmacol 66:1627-34
    133. Taylor SW, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S, Murphy AN, Gaucher SP, Capaldi RA, Gibson BW, Ghosh SS.2003. Characterization of the human heart mitochondrial proteome. Nat Biotechnol 21:281-6
    134. Mootha VK, Bunkenborg J, Olsen JV, Hjerrild M, Wisniewski JR, Stahl E, Bolouri MS, Ray HN, Sihag S, Kamal M, Patterson N, Lander ES, Mann M.2003. Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell 115: 629-40
    135. Heazlewood JL, Tonti-Filippini JS, Gout AM, Day DA, Whelan J, Millar AH.2004. Experimental analysis of the Arabidopsis mitochondrial proteome highlights signaling and regulatory components, provides assessment of targeting prediction programs, and indicates plant-specific mitochondrial proteins. Plant Cell 16:241-56
    136. Major T, von Janowsky B, Ruppert T, Mogk A, Voos W.2006. Proteomic analysis of mitochondrial protein turnover:identification of novel substrate proteins of the matrix protease pim1. Mol Cell Biol 26:762-76
    137. Krieg RC, Knuechel R, Schiffmann E, Liotta LA, Petricoin EF,3rd, Herrmann PC.2004. Mitochondrial proteome:cancer-altered metabolism associated with cytochrome c oxidase subunit level variation. Proteomics 4:2789-95
    138. Tsutsumi T, Matsuda M, Aizaki H, Moriya K, Miyoshi H, Fujie H, Shintani Y, Yotsuyanagi H, Miyamura T, Suzuki T, Koike K.2009. Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein. Hepatology 50:378-86
    139. Ohman T, Rintahaka J, Kalkkinen N, Matikainen S, Nyman TA.2009. Actin and RIG-I/MAVS signaling components translocate to mitochondria upon influenza A virus infection of human primary macrophages. J Immunol 182:5682-92
    140. Da Cruz S, Parone PA, Martinou JC.2005. Building the mitochondrial proteome. Expert Rev Proteomics 2:541-51
    141. Patel PC, Fisher KH, Yang EC, Deane CM, Harrison RE.2009. Proteomic analysis of microtubule-associated proteins during macrophage activation. Mol Cell Proteomics 8: 2500-14
    142. Hofmann WA, Arduini A, Nicol SM, Camacho CJ, Lessard JL, Fuller-Pace FV, de Lanerolle P. 2009. SUMOylation of nuclear actin. J Cell Biol 186:193-200
    143. Dohner K, Sodeik B.2005. The role of the cytoskeleton during viral infection. Curr Top Microbiol Immunol 285:67-108
    144. Igakura T, Stinchcombe JC, Goon PK, Taylor GP, Weber JN, Griffiths GM, Tanaka Y, Osame M, Bangham CR.2003. Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton. Science 299:1713-6
    145. Pereira AC, Leite FG, Brasil BS, Soares-Martins JA, Torres AA, Pimenta PF, Souto-Padron T, Traktman P, Ferreira PC, Kroon EG, Bonjardim CA.2012. A vaccinia virus-driven interplay between the MKK4/7-JNK1/2 pathway and cytoskeleton reorganization. J Virol 86:172-84
    146. Delorme-Axford E, Coyne CB.2011. The actin cytoskeleton as a barrier to virus infection of polarized epithelial cells. Viruses 3:2462-77
    147. Wallin E, von Heijne G.1998. Genome-wide analysis of integral membrane proteins from eubacterial, archaean, and eukaryotic organisms. Protein Sci 7:1029-38
    148. Groen AJ, Lilley KS.2010. Proteomics of total membranes and subcellular membranes. Expert Rev Proteomics 1:867-78
    149. Helbig AO, Heck AJ, Slijper M.2010. Exploring the membrane proteome--challenges and analytical strategies. J Proteomics 73:868-78
    150. Fischer F, Wolters D, Rogner M, Poetsch A.2006. Toward the complete membrane proteome: high coverage of integral membrane proteins through transmembrane peptide detection. Mol Cell Proteomics 5:444-53
    151. Ferro M, Seigneurin-Berny D, Rolland N, Chapel A, Salvi D, Garin J, Joyard J.2000. Organic solvent extraction as a versatile procedure to identify hydrophobic chloroplast membrane proteins. Electrophoresis 21:3517-26
    152. Bricker TM, Sherman LA.1984. Triton X-114 phase fractionation of membrane proteins of the cyanobacterium Anacystis nidulans R2. Arch Biochem Biophys 235:204-11
    153. Mitra SK, Gantt JA, Ruby JF, Clouse SD, Goshe MB.2007. Membrane proteomic analysis of Arabidopsis thaliana using alternative solubilization techniques. J Proteome Res 6:1933-50
    154. Ruth MC, Old WM, Emrick MA, Meyer-Arendt K, Aveline-Wolf LD, Pierce KG, Mendoza AM, Sevinsky JR, Hamady M, Knight RD, Resing KA, Ahn NG.2006. Analysis of membrane proteins from human chronic myelogenous leukemia cells:comparison of extraction methods for multidimensional LC-MS/MS. J Proteome Res 5:709-19
    155. Zahedi RP, Sickmann A, Boehm AM, Winkler C, Zufall N, Schonfisch B, Guiard B, Pfanner N, Meisinger C.2006. Proteomic analysis of the yeast mitochondrial outer membrane reveals accumulation of a subclass of preproteins. Mol Biol Cell 17:1436-50
    156. Washburn MP, Wolters D, Yates JR,3rd.2001. Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat Biotechnol 19:242-7
    157. Van Hoof D, Dormeyer W, Braam SR, Passier R, Monshouwer-Kloots J, Ward-van Oostwaard D, Heck AJ, Krijgsveld J, Mummery CL.2010. Identification of cell surface proteins for antibody-based selection of human embryonic stem cell-derived cardiomyocytes. J Proteome Res 9:1610-8
    158. Ross PL, Huang YN, Marchese JN, Williamson B, Parker K, Hattan S, Khainovski N, Pillai S, Dey S, Daniels S, Purkayastha S, Juhasz P, Martin S, Bartlet-Jones M, He F, Jacobson A, Pappin DJ.2004. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics 3:1154-69
    159. Chazal N, Gerlier D.2003. Virus entry, assembly, budding, and membrane rafts. Microbiol Mol Biol Rev 67:226-37, table of contents
    160. Xie N, Huang K, Zhang T, Lei Y, Liu R, Wang K, Zhou S, Li J, Wu J, Wu H, Deng C, Zhao X, Nice EC, Huang C.2012. Comprehensive proteomic analysis of host cell lipid rafts modified by HBV infection. J Proteomics 75:725-39
    161. Waheed AA, Freed EO.2009. Lipids and membrane microdomains in HIV-1 replication. Virus Res 143:162-76
    162. Taylor RS, Wu CC, Hays LG, Eng JK, Yates JR,3rd, Howell KE.2000. Proteomics of rat liver Golgi complex:minor proteins are identified through sequential fractionation. Electrophoresis 21:3441-59
    163. Tadolini B, Zanotti M.1982. Isolation of a Golgi rich fraction from rat ventral prostate. Ital J Biochem 31:139-50
    164. Engel S, de Vries M, Herrmann A, Veit M.2012. Mutation of a raft-targeting signal in the transmembrane region retards transport of influenza virus hemagglutinin through the Golgi. FEBSLett 586:277-82
    165. Jauka T, Mutsvunguma L, Boshoff A, Edkins AL, Knox C.2010. Localisation of Theiler's murine encephalomyelitis virus protein 2C to the Golgi apparatus using antibodies generated against a peptide region. J Virol Methods 168:162-9
    166. Wu CC, Howell KE, Neville MC, Yates JR,3rd, McManaman JL.2000. Proteomics reveal a link between the endoplasmic reticulum and lipid secretory mechanisms in mammary epithelial cells. Electrophoresis 21:3470-82
    167. Galeva N, Altermann M.2002. Comparison of one-dimensional and two-dimensional gel electrophoresis as a separation tool for proteomic analysis of rat liver microsomes: cytochromes P450 and other membrane proteins. Proteomics 2:713-22
    168. Han DK, Eng J, Zhou H, Aebersold R.2001. Quantitative profiling of differentiation-induced microsomal proteins using isotope-coded affinity tags and mass spectrometry. Nat Biotechnol 19:946-51
    169. Epel BL.2009. Plant viruses spread by diffusion on ER-associated movement-protein-rafts through plasmodesmata gated by viral induced host beta-1,3-glucanases. Semin Cell Dev Biol 20:1074-81
    170. Pierini R, Cottam E, Roberts R, Wileman T.2009. Modulation of membrane traffic between endoplasmic reticulum, ERGIC and Golgi to generate compartments for the replication of bacteria and viruses. Semin Cell Dev Biol 20:828-33
    171. Geraghty MT, Bassett D, Morrell JC, Gatto GJ, Jr., Bai J, Geisbrecht BV, Hieter P, Gould SJ. 1999. Detecting patterns of protein distribution and gene expression in silico. Proc Natl Acad Sci USA 96:2937-42
    172. Fukao Y, Hayashi M, Nishimura M.2002. Proteomic analysis of leaf peroxisomal proteins in greening cotyledons of Arabidopsis thaliana. Plant Cell Physiol43:689-96
    173. Schafer H, Nau K, Sickmann A, Erdmann R, Meyer HE.2001. Identification of peroxisomal membrane proteins of Saccharomyces cerevisiae by mass spectrometry. Electrophoresis 22: 2955-68
    174. Journet A, Chapel A, Kieffer S, Louwagie M, Luche S, Garin J.2000. Towards a human repertoire of monocytic lysosomal proteins. Electrophoresis 21:3411-9
    175. Journet A, Chapel A, Kieffer S, Roux F, Garin J.2002. Proteomic analysis of human lysosomes:application to monocytic and breast cancer cells. Proteomics 2:1026-40
    176. Lazarow PB.2011. Viruses exploiting peroxisomes. Curr Opin Microbiol 14:458-69
    177. Coleman EM, Walker TN, Hildreth JE.2012. Loss of Niemann Pick type C proteins 1 and 2 greatly enhances HIV infectivity and is associated with accumulation of HIV Gag and cholesterol in late endosomes/lysosomes. Virol J 9:31
    178. Ma W, Richt JA.2010. Swine influenza vaccines:current status and future perspectives. Anim Health Res Rev 11:81-96
    179. Kothalawala H, Toussaint MJ, Gruys E.2006. An overview of swine influenza. Vet Q 28: 46-53
    180. Lanari M, Capretti MG, Decembrino L, Natale F, Pedicino R, Pugni L, Serra L.2010. Focus on pandemic 2009 H1N1 influenza (swine flu). Minerva Pediatr 62:39-40
    181. Bornholdt ZA, Prasad BV.2006. X-ray structure of influenza virus NS1 effector domain. Nat Struct Mol Biol 13:559-60
    182. Murayama R, Harada Y, Shibata T, Kuroda K, Hayakawa S, Shimizu K, Tanaka T.2007. Influenza A virus non-structural protein 1 (NS1) interacts with cellular multifunctional protein nucleolin during infection. Biochem Biophys Res Commun 362:880-5
    183. Li Y, Yamakita Y, Krug RM.1998. Regulation of a nuclear export signal by an adjacent inhibitory sequence:the effector domain of the influenza virus NS1 protein. Proc Natl Acad Sci U S A 95:4864-9
    184. Garaigorta U, Falcon AM, Ortin J.2005. Genetic analysis of influenza virus NS1 gene:a temperature-sensitive mutant shows defective formation of virus particles. J Virol 79: 15246-57
    185. Ruigrok RW, Baudin F.1995. Structure of influenza virus ribonucleoprotein particles. Ⅱ. Purified RNA-free influenza virus ribonucleoprotein forms structures that are indistinguishable from the intact influenza virus ribonucleoprotein particles. J Gen Virol 76 (Pt 4):1009-14
    186. Wang TT, Palese P.2009. Unraveling the mystery of swine influenza virus. Cell 137:983-5
    187. Olsen CW.2002. The emergence of novel swine influenza viruses in North America. Virus Res 85:199-210
    188. Lemon SM, Mahmoud AA.2005. The threat of pandemic influenza:are we ready? Biosecur Bioterror 3:70-3
    189. Vijaykrishna D, Smith GJ, Pybus OG, Zhu H, Bhatt S, Poon LL, Riley S, Bahl J, Ma SK, Cheung CL, Perera RA, Chen H, Shortridge KF, Webby RJ, Webster RG, Guan Y, Peiris JS. 2011. Long-term evolution and transmission dynamics of swine influenza A virus. Nature 473: 519-22
    190. Michaelis M, Doerr HW, Cinatl J, Jr.2009. Novel swine-origin influenza A virus in humans: another pandemic knocking at the door. Med Microbiol Immunol 198:175-83
    191. Liu N, Song W, Wang P, Lee K, Chan W, Chen H, Cai Z.2008. Proteomics analysis of differential expression of cellular proteins in response to avian H9N2 virus infection in human cells. Proteomics 8:1851-8
    192. Zou W, Ke J, Zhang A, Zhou M, Liao Y, Zhu J, Zhou H, Tu J, Chen H, Jin M.2010. Proteomics analysis of differential expression of chicken brain tissue proteins in response to the neurovirulent H5N1 avian influenza virus infection. J Proteome Res 9:3789-98
    193. Coombs KM, Berard A, Xu W, Krokhin O, Meng X, Cortens JP, Kobasa D, Wilkins J, Brown EG.2010. Quantitative proteomic analyses of influenza virus-infected cultured human lung cells. J Virol 84:10888-906
    194. Vester D, Rapp E, Gade D, Genzel Y, Reichl U.2009. Quantitative analysis of cellular proteome alterations in human influenza A virus-infected mammalian cell lines. Proteomics 9: 3316-27
    195. Baas T, Baskin CR, Diamond DL, Garcia-Sastre A, Bielefeldt-Ohmann H, Tumpey TM, Thomas MJ, Carter VS, Teal TH, Van Hoeven N, Proll S, Jacobs JM, Caldwell ZR, Gritsenko MA, Hukkanen RR, Camp DG,2nd, Smith RD, Katze MG.2006. Integrated molecular signature of disease:analysis of influenza virus-infected macaques through functional genomics and proteomics. J Virol 80:10813-28
    196. Vester D, Rapp E, Kluge S, Genzel Y, Reichl U.2010. Virus-host cell interactions in vaccine production cell lines infected with different human influenza A virus variants:a proteomic approach, J Proteomics 73:1656-69
    197. Brasier AR, Spratt H, Wu Z, Boldogh I, Zhang Y, Garofalo RP, Casola A, Pashmi J, Haag A, Luxon B, Kurosky A.2004. Nuclear heat shock response and novel nuclear domain 10 reorganization in respiratory syncytial virus-infected a549 cells identified by high-resolution two-dimensional gel electrophoresis. J Virol 78:11461-76
    198. Lam YW, Evans VC, Heesom KJ, Lamond AI, Matthews DA.2010. Proteomics analysis of the nucleolus in adenovirus-infected cells. Mol Cell Proteomics 9:117-30
    199. Pinchuk GV, Lee SR, Nanduri B, Honsinger K.L, Stokes JV, Pinchuk LM.2008. Bovine viral diarrhea viruses differentially alter the expression of the protein kinases and related proteins affecting the development of infection and anti-viral mechanisms in bovine monocytes. Biochim Biophys Acta 1784:1234-47
    200. Maxwell KL, Frappier L.2007. Viral proteomics. Microbiol Mol Biol Rev 71:398-411
    201. Gorlach M, Burd CG, Portman DS, Drey fuss G.1993. The hnRNP proteins. Mol Biol Rep 18: 73-8
    202. Gustin KE, Sarnow P.2001. Effects of poliovirus infection on nucleo-cytoplasmic trafficking and nuclear pore complex composition. EMBO J 20:240-9
    203. Gupta AK, Drazba JA, Banerjee AK,1998. Specific interaction of heterogeneous nuclear ribonucleoprotein particle U with the leader RNA sequence of vesicular stomatitis virus. J Virol 72:8532-40
    204. Melen K, Kinnunen L, Fagerlund R, Ikonen N, Twu KY, Krug RM, Julkunen I.2007. Nuclear and nucleolar targeting of influenza A virus NS1 protein:striking differences between different virus subtypes. J Virol 81:5995-6006
    205. Volmer R, Mazel-Sanchez B, Volmer C, Soubies SM, Guerin JL.2010. Nucleolar localization of influenza A NS1:striking differences between mammalian and avian cells. Virol J 7:63
    206. Lee JH, Kim SH, Pascua PN, Song MS, Baek YH, Jin X, Choi JK, Kim CJ, Kim H, Choi YK. 2010. Direct interaction of cellular hnRNP-F and NS1 of influenza A virus accelerates viral replication by modulation of viral transcriptional activity and host gene expression. Virology 397:89-99
    207. Gorlach M, Burd CG, Dreyfuss G.1994. The determinants of RNA-binding specificity of the heterogeneous nuclear ribonucleoprotein C proteins. J Biol Chew 269:23074-8
    208. Gustin KE, Sarnow P.2002. Inhibition of nuclear import and alteration of nuclear pore complex composition by rhinovirus. J Virol 76:8787-96
    209. Noisakran S, Sengsai S, Thongboonkerd V, Kanlaya R, Sinchaikul S, Chen ST, Puttikhunt C, Kasinrerk W, Limjindaporn T, Wongwiwat W, Malasit P, Yenchitsomanus PT.2008. Identification of human hnRNP C1/C2 as a dengue virus NS1-interacting protein. Biochem Biophys Res Commun 372:67-72
    210. Munday DC, Hiscox JA, Barr JN.2010. Quantitative proteomic analysis of A549 cells infected with human respiratory syncytial virus subgroup B using SILAC coupled to LC-MS/MS. Proteomics 10:4320-34
    211. Piccoli C, Scrima R, D'Aprile A, Ripoli M, Lecce L, Boffoli D, Capitanio N.2006. Mitochondrial dysfunction in hepatitis C virus infection. Biochim Biophys Acta 1757:1429-37
    212. Arrigo AP.2011. Structure-functions of HspB1 (Hsp27). Methods Mol Biol 787:105-19
    213. Alfonso P, Rivera J, Hernaez B, Alonso C, Escribano JM.2004. Identification of cellular proteins modified in response to African swine fever virus infection by proteomics. Proteomics 4:2037-46
    214. Zheng X, Hong L, Shi L, Guo J, Sun Z, Zhou J.2008. Proteomics analysis of host cells infected with infectious bursal disease virus. Mol Cell Proteomics 7:612-25
    215. Mosser DD, Morimoto RI.2004. Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907-18
    216. Haller O, Kochs G.2002. Interferon-induced mx proteins:dynamin-like GTPases with antiviral activity. Traffic 3:710-7
    217. Tan J, Qiao W, Wang J, Xu F, Li Y, Zhou J, Chen Q, Geng Y.2008. IFP35 is involved in the antiviral function of interferon by association with the viral tas transactivator of bovine foamy virus. J Virol 82:4275-83
    218. Davila S, Froeling FE, Tan A, Bonnard C, Boland GJ, Snippe H, Hibberd ML, Seielstad M. 2010. New genetic associations detected in a host response study to hepatitis B vaccine. Genes Immun 11:232-8
    219. Zhang L, Tang Y, Tie Y, Tian C, Wang J, Dong Y, Sun Z, He F.2007. The PH domain containing protein CKIP-1 binds to IFP35 and Nmi and is involved in cytokine signaling. Cell Signal 19:932-44
    220. Fillmore RA, Mitra A, Xi Y, Ju J, Scammell J, Shevde LA, Samant RS.2009. Nmi (N-Myc interactor) inhibits Wnt/beta-catenin signaling and retards tumor growth. Int J Cancer 125: 556-64
    221. Lee ND, Chen J, Shpall RL, Naumovski L.1999. Subcellular localization of interferon-inducible Myc/stat-interacting protein Nmi is regulated by a novel IFP 35 homologous domain. J Interferon Cytokine Res 19:1245-52
    222. Zhou X, Liao J, Meyerdierks A, Feng L, Naumovski L, Bottger EC, Omary MB.2000. Interferon-alpha induces nmi-IFP35 heterodimeric complex formation that is affected by the phosphorylation of IFP35. J Biol Chem 275:21364-71
    223. Kisselev L, Frolova L, Haenni AL.1993. Interferon inducibility of mammalian tryptophanyl-tRNA synthetase:new perspectives. Trends Biochem Sci 18:263-7
    224. Kim KI, Giannakopoulos NV, Virgin HW, Zhang DE.2004. Interferon-inducible ubiquitin E2, Ubc8, is a conjugating enzyme for protein ISGylation. Mol Cell Biol 24:9592-600
    225. Werneke SW, Schilte C, Rohatgi A, Monte KJ, Michault A, Arenzana-Seisdedos F, Vanlandingham DL, Higgs S, Fontanet A, Albert ML, Lenschow DJ.2011. ISG15 is critical in the control of Chikungunya virus infection independent of UbEIL mediated conjugation. PLoS Pathog 7:e1002322
    226. Guan R, Ma LC, Leonard PG, Amer BR, Sridharan H, Zhao C, Krug RM, Montelione GT. 2011. Structural basis for the sequence-specific recognition of human ISG15 by the NS1 protein of influenza B virus. Proc Natl Acad Sci U S A 108:13468-73
    227. Billharz R, Zeng H, Proll SC, Korth MJ, Lederer S, Albrecht R, Goodman AG, Rosenzweig E, Tumpey TM, Garcia-Sastre A, Katze MG.2009. The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways. J Virol 83:10557-70
    228. Safronetz D, Rockx B, Feldmann F, Belisle SE, Palermo RE, Brining D, Gardner D, Proll SC, Marzi A, Tsuda Y, Lacasse RA, Kercher L, York A, Korth MJ, Long D, Rosenke R, Shupert WL, Aranda CA, Mattoon JS. Kobasa D, Kobinger G, Li Y, Taubenberger JK, Richt JA, Parnell M, Ebihara H, Kawaoka Y, Katze MG, Feldmann H.2011. Pandemic swine-origin H1N1 influenza A virus isolates show heterogeneous virulence in macaques. J Virol 85: 1214-23
    229. Ma W, Belisle SE, Mosier D, Li X, Stigger-Rosser E, Liu Q, Qiao C, Elder J, Webby R, Katze MG, Richt JA.2011.2009 pandemic H1N1 influenza virus causes disease and upregulation of genes related to inflammatory and immune responses, cell death, and lipid metabolism in pigs. J Virol 85:11626-37
    230. Chan RB, Tanner L, Wenk MR.2010. Implications for lipids during replication of enveloped viruses. Chem Phys Lipids 163:449-59
    231. Heaton NS, Randall G.2011. Multifaceted roles for lipids in viral infection. Trends Microbiol 19:368-75
    232. Xiao T, Shoeb M, Siddiqui MS, Zhang M, Ramana KV, Srivastava SK, Vasiliou V, Ansari NH. 2009. Molecular cloning and oxidative modification of human lens ALDH1A1:implication in impaired detoxification of lipid aldehydes. J Toxicol Environ Health A 72:577-84
    233. Martinelli E, Tharinger H, Frank I, Arthos J, Piatak M, Jr., Lifson JD, Blanchard J, Gettie A, Robbiani M.2011.HSV-2 infection of dendritic cells amplifies a highly susceptible HIV-1 cell target. PLoS Pat hog 7:e 1002109
    234. Kalinec F, Webster P, Maricle A, Guerrero D, Chakravarti DN, Chakravarti B, Gellibolian R, Kalinec G.2009. Glucocorticoid-stimulated, transcription-independent release of annexin A1 by cochlear Hensen cells. Br J Pharmacol 158:1820-34
    235. Kamal AM, Smith SF, De Silva Wijayasinghe M, Solito E, Corrigan CJ.2001. An annexin 1 (ANXA1)-derived peptide inhibits prototype antigen-driven human T cell Thl and Th2 responses in vitro. Clin Exp Allergy 31:1116-25
    236. Ohta A, Nishiyama Y.2011. Mitochondria and viruses. Mitochondrion 11:1-12
    237. Bonawitz ND, Clayton DA, Shadel GS.2006. Initiation and beyond:multiple functions of the human mitochondrial transcription machinery. Mol Cell 24:813-25
    238. Soubannier V, McBride HM.2009. Positioning mitochondrial plasticity within cellular signaling cascades. Biochim Biophys Acta 1793:154-70
    239. West AP, Shadel GS, Ghosh S.2011. Mitochondria in innate immune responses. Nat Rev Immunol 11:389-402
    240. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S. 2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6:981-8
    241. Seth RB, Sun L, Ea CK, Chen ZJ.2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122: 669-82
    242. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB.2005. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19:727-40
    243. Moore CB, Bergstralh DT, Duncan JA, Lei Y, Morrison TE, Zimmermann AG, Accavitti-Loper MA, Madden VJ, Sun L, Ye Z, Lich JD, Heise MT, Chen Z, Ting JP.2008. NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451:573-7
    244. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J.2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167-72
    245. Mibayashi M, Martinez-Sobrido L, Loo YM, Cardenas WB, Gale M, Jr., Garcia-Sastre A. 2007. Inhibition of retinoic acid-inducible gene Ⅰ-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol 81:514-24
    246. Chanturiya AN, Basanez G, Schubert U, Henklein P, Yewdell JW, Zimmerberg J.2004. PB1-F2, an influenza A virus-encoded proapoptotic mitochondrial protein, creates variably sized pores in planar lipid membranes. J Virol 78:6304-12
    247. Jacotot E, Ravagnan L, Loeffler M, Ferri KF, Vieira HL, Zamzami N, Costantini P, Druillennec S, Hoebeke J, Briand JP, Irinopoulou T, Daugas E, Susin SA, Cointe D, Xie ZH, Reed JC, Roques BP, Kroemer G.2000. The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore. J Exp Med 191:33-46
    248. Lund K, Ziola B.1986. Synthesis of mitochondrial macromolecules in herpes simplex type 1 virus infected Vero cells. Biochem Cell Biol 64:1303-9
    249. Liu J, Wei T, Kwang J.2002. Avian encephalomyelitis virus induces apoptosis via major structural protein VP3. Virology 300:39-49
    250. Wang G, Barrett JW, Nazarian SH, Everett H, Gao X, Bleackley C, Colwill K, Moran MF, McFadden G.2004. Myxoma virus M11L prevents apoptosis through constitutive interaction with Bak. J Virol 78:7097-111
    251. Wang HW, Sharp TV, Koumi A, Koentges G, Boshoff C.2002. Characterization of an anti-apoptotic glycoprotein encoded by Kaposi's sarcoma-associated herpesvirus which resembles a spliced variant of human survivin. EMBO J 21:2602-15
    252. Diamond DL, Jacobs JM, Paeper B, Proll SC, Gritsenko MA, Carithers RL, Jr., Larson AM, Yeh MM, Camp DG,2nd, Smith RD, Katze MG.2007. Proteomic profiling of human liver biopsies:hepatitis C virus-induced fibrosis and mitochondrial dysfunction. Hepatology 46: 649-57
    253. Rasmussen AL, Diamond DL, McDermott JE, Gao X, Metz TO, Matzke MM, Carter VS, Belisle SE, Korth MJ, Waters KM, Smith RD, Katze MG.2011. Systems virology identifies a mitochondrial fatty acid oxidation enzyme, dodecenoyl coenzyme A delta isomerase, required for hepatitis C virus replication and likely pathogenesis. J Virol 85:11646-54
    254. Spurgers KB, Alefantis T, Peyser BD, Ruthel GT, Bergeron AA, Costantino JA, Enterlein S, Kota KP, Boltz RC, Aman MJ, Delvecchio VG, Bavari S.2010. Identification of essential filovirion-associated host factors by serial proteomic analysis and RNAi screen. Mol Cell Proleomics 9:2690-703
    255. Han J, Rutherford MS, Faaberg KS.2010. Proteolytic products of the porcine reproductive and respiratory syndrome virus nsp2 replicase protein. J Virol 84:10102-12
    256. Wang Q, Shu R, He H, Wang L, Ma Y, Zhu H, Wang Z, Wang S, Shen G, Lei P.2012. Co-silencing of Birc5 (survivin) and Hspa5 (Grp78) induces apoptosis in hepatoma cells more efficiently than single gene interference. Int J Oncol
    257. Cilloniz C, Pantin-Jackwood MJ, Ni C, Carter VS, Korth MJ, Swayne DE, Tumpey TM, Katze MG.2012. Molecular signatures associated with Mx1-mediated resistance to highly pathogenic influenza virus infection:mechanisms of survival. J Virol 86:2437-46
    258. Liao W, Goh FY, Betts RJ, Kemeny DM, Tam J, Bay BH, Wong WS.2011. A novel anti-apoptotic role for apolipoprotein L2 in IFN-gamma-induced cytotoxicity in human bronchial epithelial cells. J Cell Physiol 226:397-406
    259. Ran Q, Wadhwa R, Kawai R, Kaul SC, Sifers RN, Bick RJ, Smith JR, Pereira-Smith OM. 2000. Extramitochondrial localization of mortalin/mthsp70/PBP74/GRP75. Biochem Biophys Res Commun 275:174-9
    260. Kimura K, Tanaka N, Nakamura N, Takano S, Ohkuma S.2007. Knockdown of mitochondrial heat shock protein 70 promotes progeria-like phenotypes in caenorhabditis elegans. J Biol Chem 282:5910-8
    261. Vu MT, Zhai P, Lee J, Guerra C, Liu S, Gustin MC, Silberg JJ.2012. The DNLZ/HEP zinc-binding subdomain is critical for regulation of the mitochondrial chaperone HSPA9. Protein Sci 21:258-67
    262. Jeon JP, Kim JW, Park B, Nam HY, Shim SM, Lee MH, Han BG.2008. Identification of tumor necrosis factor signaling-related proteins during Epstein-Barr virus-induced B cell transformation. Acta Virol 52:151-9
    263. Fislova T, Thomas B, Graef KM, Fodor E.2010. Association of the influenza virus RNA polymerase subunit PB2 with the host chaperonin CCT. J Virol 84:8691-9
    264. de Melker AA, Sonnenberg A.1999. Integrins:alternative splicing as a mechanism to regulate ligand binding and integrin signaling events. Bioessays 21:499-509
    265. Izmailyan R, Hsao JC, Chung CS, Chen CH, Hsu PW, Liao CL, Chang W.2012. Integrin betal Mediates Vaccinia Virus Entry through Activation of PI3K/Akt Signaling. J Virol
    266. Gianni T, Campadelli-Fiume G.2012. alphaVbeta3-integrin relocalizes nectinl and routes herpes simplex virus to lipid rafts. J Virol 86:2850-5
    267. Bowles J, Steain M, Slobedman B, Abendroth A.2012. Inhibition of integrin alpha 6 expression by cell-free varicella zoster virus. J Gen Virol
    268. Lee JW, Liao PC, Young KC, Chang CL, Chen SS, Chang TT, Lai MD, Wang SW.2011. Identification of hnRNPH1, NF45, and C14orf166 as novel host interacting partners of the mature hepatitis C virus core protein. JProteome Res 10:4522-34
    269. Valente ST, Gilmartin GM, Mott C, Falkard B, Goff SP.2009. Inhibition of HIV-1 replication by eIF3f. Proc Natl Acad Sci USA 106:4071-8
    270. Zheng SQ, Li YX, Zhang Y, Li X, Tang H.2011. MiR-101 regulates HSV-1 replication by targeting ATP5B. Antiviral Res 89:219-26

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