Silencing suppressors: viral weapons for countering host cell defenses

Abstract

RNA silencing is a conserved eukaryotic pathway involved in the suppression of gene expression via sequence-specific interactions that are mediated by 21–23 nt RNA molecules. During infection, RNAi can act as an innate immune system to defend against viruses. As a counter-defensive strategy, silencing suppressors are encoded by viruses to inhibit various stages of the silencing process. These suppressors are diverse in sequence and structure and act via different mechanisms. In this review, we discuss whether RNAi is a defensive strategy in mammalian host cells and whether silencing suppressors can be encoded by mammalian viruses. We also review the modes of action proposed for some silencing suppressors.

Keywords

RNA interference (RNAi) / silencing suppressors / mammalian virus

References

[1] Anandalakshmi, R., Marathe, R., Ge, X., Herr, J.M. Jr, Mau, C., Mallory, A., Pruss, G., Bowman, L., and Vance, V.B. (2000). A calmodulin-related protein that suppresses posttranscriptional gene silencing in plants. Science 290, 142–144 .11021800
[2] Anandalakshmi, R., Pruss, G.J., Ge, X., Marathe, R., Mallory, A.C., Smith, T.H., and Vance, V.B. (1998). A viral suppressor of gene silencing in plants. Proc Natl Acad Sci U S A 95, 13079–13084 .9789044
[3] Basler, C.F., Wang, X., Mühlberger, E., Volchkov, V., Paragas, J., Klenk, H.D., García-Sastre, A., and Palese, P. (2000). The Ebola virus VP35 protein functions as a type I IFN antagonist. Proc Natl Acad Sci U S A 97, 12289–12294 .11027311
[4] Basu, A., Meyer, K., Ray, R.B., and Ray, R. (2001). Hepatitis C virus core protein modulates the interferon-induced transacting factors of Jak/Stat signaling pathway but does not affect the activation of downstream IRF-1 or 561 gene. Virology 288, 379–390 .11601909
[5] Beattie, E., Kauffman, E.B., Martinez, H., Perkus, M.E., Jacobs, B.L., Paoletti, E., and Tartaglia, J. (1996). Host-range restriction of vaccinia virus E3L-specific deletion mutants. Virus Genes 12, 89–94 .8879125
[6] Bennasser, Y., Le, S.Y., Benkirane, M., and Jeang, K.T. (2005). Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing. Immunity 22, 607–619 .15894278
[7] Bernstein, E., Caudy, A.A., Hammond, S.M., and Hannon, G.J. (2001). Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363–366 .11201747
[8] Brigneti, G., Voinnet, O., Li, W.X., Ji, L.H., Ding, S.W., and Baulcombe, D.C. (1998). Viral pathogenicity determinants are suppressors of transgene silencing in Nicotiana benthamiana. EMBO J 17, 6739–6746 .9822616
[9] Bucher, E., Hemmes, H., de Haan, P., Goldbach, R., and Prins, M. (2004). The influenza A virus NS1 protein binds small interfering RNAs and suppresses RNA silencing in plants. J Gen Virol 85, 983–991 .15039540
[10] Bucher, E., Sijen, T., De Haan, P., Goldbach, R., and Prins, M. (2003). Negative-strand tospoviruses and tenuiviruses carry a gene for a suppressor of gene silencing at analogous genomic positions. J Virol 77, 1329–1336 .12502849
[11] Cantaluppi, V., Biancone, L., Boccellino, M., Doublier, S., Benelli, R., Carlone, S., Albini, A., and Camussi, G. (2001). HIV type 1 Tat protein is a survival factor for Kaposi’s sarcoma and endothelial cells. AIDS Res Hum Retroviruses 17, 965–976 .11461682
[12] Chang, H.W., and Jacobs, B.L. (1993). Identification of a conserved motif that is necessary for binding of the vaccinia virus E3L gene products to double-stranded RNA. Virology 194, 537–547 .8099244
[13] Chang, H.W., Uribe, L.H., and Jacobs, B.L. (1995). Rescue of vaccinia virus lacking the E3L gene by mutants of E3L. J Virol 69, 6605–6608 .7666567
[14] Chen, D., Wang, M., Zhou, S., and Zhou, Q. (2002). HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim. EMBO J 21, 6801–6810 .12486001
[15] Chen, J., Li, W.X., Xie, D., Peng, J.R., and Ding, S.W. (2004). Viral virulence protein suppresses RNA silencing-mediated defense but upregulates the role of microrna in host gene expression. Plant Cell 16, 1302–1313 .15100397
[16] Coleman, J.R. (2007). The PB1-F2 protein of Influenza A virus: increasing pathogenicity by disrupting alveolar macrophages. Virol J 4, 9.17224071
[17] Delgadillo, M.O., Sáenz, P., Salvador, B., García, J.A., and Simón-Mateo, C. (2004). Human influenza virus NS1 protein enhances viral pathogenicity and acts as an RNA silencing suppressor in plants. J Gen Virol 85, 993–999 .15039541
[18] Ding, S.W. (2010). RNA-based antiviral immunity. Nat Rev Immunol 10, 632–644 .20706278
[19] Ding, S.W., and Voinnet, O. (2007). Antiviral immunity directed by small RNAs. Cell 130, 413–426 .17693253
[20] Dunoyer, P., Lecellier, C.H., Parizotto, E.A., Himber, C., and Voinnet, O. (2004). Probing the microRNA and small interfering RNA pathways with virus-encoded suppressors of RNA silencing. Plant Cell 16, 1235–1250 .15084715
[21] Dunoyer, P., Pfeffer, S., Fritsch, C., Hemmer, O., Voinnet, O., and Richards, K.E. (2002). Identification, subcellular localization and some properties of a cysteine-rich suppressor of gene silencing encoded by peanut clump virus. Plant J 29, 555–567 .11874569
[22] El Kharroubi, A., Piras, G., Zensen, R., and Martin, M.A. (1998). Transcriptional activation of the integrated chromatin-associated human immunodeficiency virus type 1 promoter. Mol Cell Biol 18, 2535–2544 .9566873
[23] Epie, N., Ammosova, T., Sapir, T., Voloshin, Y., Lane, W.S., Turner, W., Reiner, O., and Nekhai, S. (2005). HIV-1 Tat interacts with LIS1 protein. Retrovirology 2, 6.15698475
[24] Haasnoot, J., de Vries, W., Geutjes, E.J., Prins, M., de Haan, P., and Berkhout, B. (2007). The Ebola virus VP35 protein is a suppressor of RNA silencing. PLoS Pathog 3, e86.17590081
[25] Hartitz, M.D., Sunter, G., and Bisaro, D.M. (1999). The tomato golden mosaic virus transactivator (TrAP) is a single-stranded DNA and zinc-binding phosphoprotein with an acidic activation domain. Virology 263, 1–14 .10544077
[26] Hartman, A.L., Towner, J.S., and Nichol, S.T. (2004). A C-terminal basic amino acid motif of Zaire ebolavirus VP35 is essential for type I interferon antagonism and displays high identity with the RNA-binding domain of another interferon antagonist, the NS1 protein of influenza A virus. Virology 328, 177–184 .15464838
[27] Herrmann, C.H., and Rice, A.P.( 1995). Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor. J Virol 69, 1612–1620 .7853496
[28] Huang, J., Wang, F., Argyris, E., Chen, K., Liang, Z., Tian, H., Huang, W., Squires, K., Verlinghieri, G., and Zhang, H. (2007). Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med 13, 1241–1247 .17906637
[29] Isel, C., and Karn, J. (1999). Direct evidence that HIV-1 Tat stimulates RNA polymerase II carboxyl-terminal domain hyperphosphorylation during transcriptional elongation. J Mol Biol 290, 929–941 .10438593
[30] Kasschau, K.D., and Carrington, J.C. (1998). A counterdefensive strategy of plant viruses: suppression of posttranscriptional gene silencing. Cell 95, 461–470 .9827799
[31] Kasschau, K.D., Cronin, S., and Carrington, J.C. (1997). Genome amplification and long-distance movement functions associated with the central domain of tobacco etch potyvirus helper component-proteinase. Virology 228, 251–262 .9123832
[32] Kasschau, K.D., Xie, Z., Allen, E., Llave, C., Chapman, E.J., Krizan, K.A., and Carrington, J.C. (2003). P1/HC-Pro, a viral suppressor of RNA silencing, interferes with Arabidopsis development and miRNA unction. Dev Cell 4, 205–217 .12586064
[33] Kiernan, R.E., Vanhulle, C., Schiltz, L., Adam, E., Xiao, H., Maudoux, F., Calomme, C., Burny, A., Nakatani, Y., Jeang, K.T., (1999). HIV-1 tat transcriptional activity is regulated by acetylation. EMBO J 18, 6106–6118 .10545121
[34] Kok, K.H., and Jin, D.Y. (2006). Influenza A virus NS1 protein does not suppress RNA interference in mammalian cells. J Gen Virol 87, 2639–2644 .16894203
[35] Kubota, K., Tsuda, S., Tamai, A., and Meshi, T. (2003). Tomato mosaic virus replication protein suppresses virus-targeted posttranscriptional gene silencing. J Virol 77, 11016–11026 .14512550
[36] Kubota, T., Yokosawa, N., Yokota, S., and Fujii, N. (2002). Association of mumps virus V protein with RACK1 results in dissociation of STAT-1 from the alpha interferon receptor complex. J Virol 76, 12676–12682 .12438593
[37] Lakatos, L., Szittya, G., Silhavy, D., and Burgyán, J. (2004). Molecular mechanism of RNA silencing suppression mediated by p19 protein of tombusviruses. EMBO J 23, 876–884 .14976549
[38] Langland, J.O., and Jacobs, B.L. (2002). The role of the PKR-inhibitory genes, E3L and K3L, in determining vaccinia virus host range. Virology 299, 133–141 .12167348
[39] Langland, J.O., Kash, J.C., Carter, V., Thomas, M.J., Katze, M.G., and Jacobs, B.L. (2006). Suppression of proinflammatory signal transduction and gene expression by the dual nucleic acid binding domains of the vaccinia virus E3L proteins. J Virol 80, 10083–10095 .17005686
[40] Lecellier, C.H., Dunoyer, P., Arar, K., Lehmann-Che, J., Eyquem, S., Himber, C., Sa?b, A., and Voinnet, O. (2005). A cellular microRNA mediates antiviral defense in human cells. Science 308, 557–560 .15845854
[41] Li, H., Li, W.X., and Ding, S.W. (2002). Induction and suppression of RNA silencing by an animal virus. Science 296, 1319–1321 .12016316
[42] Li, W.X., Li, H., Lu, R., Li, F., Dus, M., Atkinson, P., Brydon, E.W., Johnson, K.L., García-Sastre, A., Ball, L.A., (2004). Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing. Proc Natl Acad Sci U S A 101, 1350–1355 .14745017
[43] Lin, J., and Cullen, B.R.( 2007). Analysis of the interaction of primate retroviruses with the human RNA interference machinery. J Virol 81, 12218–12226 .17855543
[44] Liu, L., Grainger, J., Ca?izares, M.C., Angell, S.M., and Lomonossoff, G.P. (2004). Cowpea mosaic virus RNA-1 acts as an amplicon whose effects can be counteracted by a RNA-2-encoded suppressor of silencing. Virology 323, 37–48 .15165817
[45] Liu, Y., Li, J., Kim, B.O., Pace, B.S., and He, J.J. (2002). HIV-1 Tat protein-mediated transactivation of the HIV-1 long terminal repeat promoter is potentiated by a novel nuclear Tat-interacting protein of 110 kDa, Tip110. J Biol Chem 277, 23854–23863 .11959860
[46] Lu, R., Folimonov, A., Shintaku, M., Li, W.X., Falk, B.W., Dawson, W.O., and Ding, S.W. (2004). Three distinct suppressors of RNA silencing encoded by a 20-kb viral RNA genome. Proc Natl Acad Sci U S A 101, 15742–15747 .15505219
[47] Moissiard, G., and Voinnet, O. (2004). Viral suppression of RNA silencing in plants. Mol Plant Pathol 5, 71–82 .20565584
[48] Mühlberger, E., Weik, M., Volchkov, V.E., Klenk, H.D., and Becker, S. (1999). Comparison of the transcription and replication strategies of marburg virus and Ebola virus by using artificial replication systems. J Virol 73, 2333–2342 .9971816
[49] Nath, A., Psooy, K., Martin, C., Knudsen, B., Magnuson, D.S., Haughey, N., and Geiger, J.D.( 1996). Identification of a human immunodeficiency virus type 1 Tat epitope that is neuroexcitatory and neurotoxic. J Virol 70, 1475–1480 .8627665
[50] Olivieri, D., Sykora, M.M., Sachidanandam, R., Mechtler, K., and Brennecke, J. (2010). An in vivo RNAi assay identifies major genetic and cellular requirements for primary piRNA biogenesis in Drosophila. EMBO J 29, 3301–3317 .20818334
[51] Otsuka, M., Jing, Q., Georgel, P., New, L., Chen, J., Mols, J., Kang, Y.J., Jiang, Z., Du, X., Cook, R., (2007). Hypersusceptibility to vesicular stomatitis virus infection in Dicer1-deficient mice is due to impaired miR24 and miR93 expression. Immunity 27, 123–134 .17613256
[52] Pfeffer, S., Dunoyer, P., Heim, F., Richards, K.E., Jonard, G., and Ziegler-Graff, V. (2002). P0 of beet Western yellows virus is a suppressor of posttranscriptional gene silencing. J Virol 76, 6815–6824 .12050394
[53] Pfeffer, S., Sewer, A., Lagos-Quintana, M., Sheridan, R., Sander, C., Gr?sser, F.A., van Dyk, L.F., Ho, C.K., Shuman, S., Chien, M., (2005). Identification of microRNAs of the herpesvirus family. Nat Methods 2, 269–276 .15782219
[54] Pruss, G., Ge, X., Shi, X.M., Carrington, J.C., and Bowman Vance, V. (1997). Plant viral synergism: the potyviral genome encodes a broad-range pathogenicity enhancer that transactivates replication of heterologous viruses. Plant Cell 9, 859–868 .9212462
[55] Qu, F., Ren, T., and Morris, T.J. (2003). The coat protein of turnip crinkle virus suppresses posttranscriptional gene silencing at an early initiation step. J Virol 77, 511–522 .12477856
[56] Reed, J.C., Kasschau, K.D., Prokhnevsky, A.I., Gopinath, K., Pogue, G.P., Carrington, J.C., and Dolja, V.V. (2003). Suppressor of RNA silencing encoded by Beet yellows virus. Virology 306, 203–209 .12642093
[57] Reyes, C.A., De Francesco, A., Pena, E.J., Costa, N., Plata, M.I., Sendin, L., Castagnaro, A.P., and Garcia, M.L. (2011). Resistance to Citrus psorosis virus in transgenic sweet orange plants is triggered by coat protein-RNA silencing. J Biotechnol 151, 151–158 .
[58] Ruiz, M.T., Voinnet, O., and Baulcombe, D.C. (1998). Initiation and maintenance of virus-induced gene silencing. Plant Cell 10, 937–946 .9634582
[59] Rusnati, M., and Presta, M. (2002). HIV-1 Tat protein and endothelium: from protein/cell interaction to AIDS-associated pathologies. Angiogenesis 5, 141–151 .12831055
[60] Saunders, L.R., and Barber, G.N. (2003). The dsRNA binding protein family: critical roles, diverse cellular functions. FASEB J 17, 961–983 .12773480
[61] Silhavy, D., Molnár, A., Lucioli, A., Szittya, G., Hornyik, C., Tavazza, M., and Burgyán, J. (2002). A viral protein suppresses RNA silencing and binds silencing-generated, 21- to 25-nucleotide double-stranded RNAs. EMBO J 21, 3070–3080 .12065420
[62] Song, L., Liu, H., Gao, S., Jiang, W., and Huang, W. (2010). Cellular microRNAs inhibit replication of the H1N1 influenza A virus in infected cells. J Virol 84, 8849–8860 .20554777
[63] Takeda, A., Sugiyama, K., Nagano, H., Mori, M., Kaido, M., Mise, K., Tsuda, S., and Okuno, T. (2002). Identification of a novel RNA silencing suppressor, NSs protein of Tomato spotted wilt virus. FEBS Lett 532, 75–79 .12459466
[64] Thomas, C.L., Leh, V., Lederer, C., and Maule, A.J. (2003). Turnip crinkle virus coat protein mediates suppression of RNA silencing in Nicotiana benthamiana. Virology 306, 33–41 .12620795
[65] van Rij, R.P. (2008). Virus meets RNAi. Symposium on antiviral applications of RNA interference. EMBO Rep 9, 725–729 .18636088
[66] Van Wezel, R., Liu, H., Wu, Z., Stanley, J., and Hong, Y. (2003). Contribution of the zinc finger to zinc and DNA binding by a suppressor of posttranscriptional gene silencing. J Virol 77, 696–700 .12477872
[67] van, W.R., Dong, X., Liu, H., Tien, P., Stanley, J., and Hong, Y. (2002). Mutation of three cysteine residues in Tomato yellow leaf curl virus-China C2 protein causes dysfunction in pathogenesis and posttranscriptional gene-silencing suppression. Mol Plant Microbe Interact 15, 203–208 .11952122
[68] Vance, V.B.( 1991). Replication of potato virus X RNA is altered in coinfections with potato virus Y. Virology 182, 486–494 .2024486
[69] Voinnet, O., Lederer, C., and Baulcombe, D.C. (2000). A viral movement protein prevents spread of the gene silencing signal in Nicotiana benthamiana. Cell 103, 157–167 .11051555
[70] Voinnet, O., Pinto, Y.M., and Baulcombe, D.C. (1999). Suppression of gene silencing: a general strategy used by diverse DNA and RNA viruses of plants. Proc Natl Acad Sci U S A 96, 14147–14152 .10570213
[71] Wang, Y., Kato, N., Jazag, A., Dharel, N., Otsuka, M., Taniguchi, H., Kawabe, T., and Omata, M. (2006). Hepatitis C virus core protein is a potent inhibitor of RNA silencing-based antiviral response. Gastroenterology 130, 883–892 .16530526
[72] Yang, X., Gold, M.O., Tang, D.N., Lewis, D.E., Aguilar-Cordova, E., Rice, A.P., and Herrmann, C.H. (1997). TAK, an HIV Tat-associated kinase, is a member of the cyclin-dependent family of protein kinases and is induced by activation of peripheral blood lymphocytes and differentiation of promonocytic cell lines. Proc Natl Acad Sci U S A 94, 12331–12336 .9356449
[73] Yelina, N.E., Savenkov, E.I., Solovyev, A.G., Morozov, S.Y., and Valkonen, J.P.( 2002). Long-distance movement, virulence, and RNA silencing suppression controlled by a single protein in hordei- and potyviruses: complementary functions between virus families. J Virol 76, 12981–12991 .12438624
[74] Zamore, P.D., Tuschl, T., Sharp, P.A., and Bartel, D.P. (2000). RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101, 25–33 .10778853