Abstract
Interferon (IFN)-mediated pathways are a crucial part of the cellular response against viral infection. Type III IFNs, which include IFN-λ1, 2 and 3, mediate antiviral responses similar to Type I IFNs via a distinct receptor complex. IFN-λ1 is more effective than the other two members. Transcription of IFN-λ1 requires activation of IRF3/7 and nuclear factor-kappa B (NF-κB), similar to the transcriptional mechanism of Type I IFNs. Using reporter assays, we discovered that viral infection induced both IFN-λ1 promoter activity and that of the 3′-untranslated region (UTR), indicating that IFN-λ1 expression is also regulated at the post-transcriptional level. After analysis with microRNA (miRNA) prediction programs and 3′UTR targeting site assays, the miRNA-548 family, including miR-548b-5p, miR-548c-5p, miR-548i, miR-548j, and miR-548n, was identified to target the 3′UTR of IFN-λ1. Further study demonstrated that miRNA-548 mimics down-regulated the expression of IFN-λ1. In contrast, their inhibitors, the complementary RNAs, enhanced the expression of IFN-λ1 and IFN-stimulated genes. Furthermore, miRNA-548 mimics promoted infection by enterovirus-71 (EV71) and vesicular stomatitis virus (VSV), whereas their inhibitors significantly suppressed the replication of EV71 and VSV. Endogenous miRNA-548 levels were suppressed during viral infection. In conclusion, our results suggest that miRNA-548 regulates host antiviral response via direct targeting of IFN-λ1, which may offer a potential candidate for antiviral therapy.
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Almeida, G.M., de Oliveira, D.B., Magalhaes, C.L., Bonjardim, C.A., Ferreira, P.C., and Kroon, E.G. (2008). Antiviral activity of type I interferons and interleukins 29 and 28a (type III interferons) against Apeu virus. Antiviral Res 80, 302–308.
Ank, N., West, H., Bartholdy, C., Eriksson, K., Thomsen, A.R., and Paludan, S.R. (2006). Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol 80, 4501–4509.
Bandi, P., Pagliaccetti, N.E., and Robek, M.D. (2010). Inhibition of type III interferon activity by orthopoxvirus immunomodulatory proteins. J Interferon Cytokine Res 30, 123–134.
Bartel, D.P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297.
Bigger, C.B., Brasky, K.M., and Lanford, R.E. (2001). DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J Virol 75, 7059–7066.
Chen, C., Ridzon, D.A., Broomer, A.J., Zhou, Z., Lee, D.H., Nguyen, J.T., Barbisin, M., Xu, N.L., Mahuvakar, V.R., Andersen, M.R., et al. (2005). Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 33, e179.
Conklin, D.C., Grant, F.J., Rixon, M.W., and Kindsvogel, W. (2002). Interferon-ɛ. U.S. Patent 6329175.
Doench, J.G., and Sharp, P.A. (2004). Specificity of microRNA target selection in translational repression. Genes Dev 18, 504–511.
Farber, J.M. (1990). A macrophage mRNA selectively induced by gamma-interferon encodes a member of the platelet factor 4 family of cytokines. Proc Natl Acad Sci U S A 87, 5238–5242.
Gack, M.U., Shin, Y.C., Joo, C.H., Urano, T., Liang, C., Sun, L., Takeuchi, O., Akira, S., Chen, Z., Inoue, S., et al. (2007). TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916–920.
Grishok, A., Pasquinelli, A.E., Conte, D., Li, N., Parrish, S., Ha, I., Baillie, D.L., Fire, A., Ruvkun, G., and Mello, C.C. (2001). Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106, 23–34.
Hong, S.H., Cho, O., Kim, K., Shin, H.J., Kotenko, S.V., and Park, S. (2007). Effect of interferon-lambda on replication of hepatitis B virus in human hepatoma cells. Virus Res 126, 245–249.
Huang, J., Wang, Y., Guo, Y., and Sun, S. (2010). Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology 52, 60–70.
Hutvagner, G., McLachlan, J., Pasquinelli, A.E., Balint, E., Tuschl, T., and Zamore, P.D. (2001). A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293, 834–838.
Hutvagner, G., and Zamore, P.D. (2002). A microRNA in a multiple-turnover RNAi enzyme complex. Science 297, 2056–2060.
Ji, Y., He, Y., Liu, L., and Zhong, X. (2010). MiRNA-26b regulates the expression of cyclooxygenase-2 in desferrioxamine-treated CNE cells. FEBS Lett 584, 961–967.
Kotenko, S.V., Gallagher, G., Baurin, V.V., Lewis-Antes, A., Shen, M., Shah, N.K., Langer, J.A., Sheikh, F., Dickensheets, H., and Donnelly, R.P. (2003). IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol 4, 69–77.
LaFleur, D.W., Nardelli, B., Tsareva, T., Mather, D., Feng, P., Semenuk, M., Taylor, K., Buergin, M., Chinchilla, D., Roshke, V., et al. (2001). Interferon-kappa, a novel type I interferon expressed in human keratinocytes. J Biol Chem 276, 39765–39771.
Lee, Y., Ahn, C., Han, J., Choi, H., Kim, J., Yim, J., Lee, J., Provost, P., Radmark, O., Kim, S., et al. (2003). The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419.
Lei, X., Liu, X., Ma, Y., Sun, Z., Yang, Y., Jin, Q., He, B., and Wang, J. (2010). The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses. J Virol 84, 8051–8061.
Lei, X., Sun, Z., Liu, X., Jin, Q., He, B., and Wang, J. (2011). Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3. J Virol 85, 8811–8818.
Li, X.D., Sun, L., Seth, R.B., Pineda, G., and Chen, Z.J. (2005). Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A 102, 17717–17722.
Lin, S., Cheung, W.K., Chen, S., Lu, G., Wang, Z., Xie, D., Li, K., Lin, M.C., and Kung, H.F. (2010). Computational identification and characterization of primate-specific microRNAs in human genome. Comput Biol Chem 34, 232–241.
Loo, Y.M., Owen, D.M., Li, K., Erickson, A.K., Johnson, C.L., Fish, P.M., Carney, D.S., Wang, T., Ishida, H., Yoneyama, M., et al. (2006). Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci U S A 103, 6001–6006.
Lund, E., Guttinger, S., Calado, A., Dahlberg, J.E., and Kutay, U. (2004). Nuclear export of microRNA precursors. Science 303, 95–98.
Maher, S.G., Sheikh, F., Scarzello, A.J., Romero-Weaver, A.L., Baker, D.P., Donnelly, R.P., and Gamero, A.M. (2008). IFNalpha and IFNlambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity. Cancer Biol Ther 7, 1109–1115.
Marukian, S., Andrus, L., Sheahan, T.P., Jones, C.T., Charles, E.D., Ploss, A., Rice, C.M., and Dustin, L.B. (2011). Hepatitis C virus induces interferon-lambda and interferon-stimulated genes in primary liver cultures. Hepatology 54, 1913–1923.
Milliken, E.L., Zhang, X., Flask, C., Duerk, J.L., MacDonald, P.N., and Keri, R.A. (2005). EB1089, a vitamin D receptor agonist, reduces proliferation and decreases tumor growth rate in a mouse model of hormone-induced mammary cancer. Cancer Lett 229, 205–215.
Muller, U., Steinhoff, U., Reis, L.F., Hemmi, S., Pavlovic, J., Zinkernagel, R.M., and Aguet, M. (1994). Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921.
Osterlund, P.I., Pietila, T.E., Veckman, V., Kotenko, S.V., and Julkunen, I. (2007). IFN regulatory factor family members differentially regulate the expression of type III IFN (IFN-lambda) genes. J Immunol 179, 3434–3442.
Park, H., Serti, E., Eke, O., Muchmore, B., Prokunina-Olsson, L., Capone, S., Folgori, A., and Rehermann, B. (2012). IL-29 is the dominant type III interferon produced by hepatocytes during acute hepatitis C virus infection. Hepatology. (In Press).
Pasquinelli, C., Lauré, F., Chatenoud, L., Beaurin, G., Gazengel, C., Bismuth, H., Degos, F., Tiollais, P., Bach, J., and Bréchot, C. (1986). Hepatitis B virus DNA in mononuclear blood cells. A frequent event in hepatitis B surface antigen-positive and -negative patients with acute and chronic liver disease. J Hepatol 3, 95–103.
Pestka, S. (1997). The human interferon-alpha species and hybrid proteins. Semin Oncol 24, S9-4–S9-17.
Piriyapongsa, J., and Jordan, I.K. (2007). A family of human microRNA genes from miniature inverted-repeat transposable elements. PLoS One 2, e203.
Robek, M.D., Boyd, B.S., and Chisari, F.V. (2005). Lambda interferon inhibits hepatitis B and C virus replication. J Virol 79, 3851–3854.
Sarasin-Filipowicz, M., Oakeley, E.J., Duong, F.H., Christen, V., Terracciano, L., Filipowicz, W., and Heim, M.H. (2008). Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A 105, 7034–7039.
Saxena, S., Jonsson, Z.O., and Dutta, A. (2003). Small RNAs with imperfect match to endogenous mRNA repress translation. Implications for off-target activity of small inhibitory RNA in mammalian cells. J Biol Chem 278, 44312–44319.
Sheppard, P., Kindsvogel, W., Xu, W., Henderson, K., Schlutsmeyer, S., Whitmore, T.E., Kuestner, R., Garrigues, U., Birks, C., Roraback, J., et al. (2003). IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol 4, 63–68.
Siren, J., Pirhonen, J., Julkunen, I., and Matikainen, S. (2005). IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29. J Immunol 174, 1932–1937.
Strillacci, A., Griffoni, C., Sansone, P., Paterini, P., Piazzi, G., Lazzarini, G., Spisni, E., Pantaleo, M.A., Biasco, G., and Tomasi, V. (2009). MiR-101 downregulation is involved in cyclooxygenase-2 overexpression in human colon cancer cells. Exp Cell Res 315, 1439–1447.
Wang, X., Li, Y., Mao, A., Li, C., and Tien, P. (2010). Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-beta induction by disrupting the VISA-associated complex. Cell Mol Immunol 7, 341–348.
Li, W., Liu, Y., Mukhtar, M.M., Gong, R., Pan, Y., Rasool, S.T., Gao, Y., Kang, L., Hao, Q., Peng, G., et al. (2008). Activation of interleukin-32 pro-inflammatory pathway in response to influenza A virus infection. PLoS ONE 3, e1985.
Yang, X.Y., Li, Y.X., Li, M., Zhang, L., Feng, L.X., and Zhang, N. (2012). Hyaluronic acid-coated nanostructured lipid carriers for targeting paclitaxel to cancer. Cancer Lett. (In Press).
Yu, Y., Gong, R., Mu, Y., Chen, Y., Zhu, C., Sun, Z., Chen, M., Liu, Y., Zhu, Y., and Wu, J. (2011). Hepatitis B virus induces a novel inflammation network involving three inflammatory factors, IL-29, IL-8, and cyclooxygenase-2. J Immunol 187, 4844–4860.
Yue, X., Wang, H., Zhao, F., Liu, S., Wu, J., Ren, W., and Zhu, Y. (2012). Hepatitis B virus-induced calreticulin protein is involved in IFN resistance. J Immunol 189, 279–286.
Zeng, Y., Yi, R., and Cullen, B.R. (2003). MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci U S A 100, 9779–9784.
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Li, Y., Xie, J., Xu, X. et al. MicroRNA-548 down-regulates host antiviral response via direct targeting of IFN-λ1. Protein Cell 4, 130–141 (2013). https://doi.org/10.1007/s13238-012-2081-y
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DOI: https://doi.org/10.1007/s13238-012-2081-y