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Published in: Archives of Virology 12/2017

01-12-2017 | Original Article

miR-146a Inhibits dengue-virus-induced autophagy by targeting TRAF6

Authors: Jieying Pu, Siyu Wu, Heping Xie, Yuye Li, Zhicong Yang, Xinwei Wu, Xi Huang

Published in: Archives of Virology | Issue 12/2017

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Abstract

During dengue virus (DENV) infection, the virus manipulates different cellular pathways to assure productive replication, including autophagy. However, it remains unclear how this autophagic process is regulated. Here, we have demonstrated a novel role for the microRNA miR-146a in negatively regulating the cellular autophagic pathway in DENV-infected A549 cells and THP-1 cells. Overexpression of miR-146a significantly blocked DENV2-induced autophagy, and LNA-mediated inhibition of miR-146a counteracted these effects. Moreover, co-overexpression of TRAF6, a target of miR-146a, significantly reversed the inhibitory effect of miR-146a on autophagy. Notably, treatment with recombinant IFN-β fully restored the autophagic activity in TRAF6-silenced cells. Furthermore, our data showed that, in DENV2-infected A549 cells, autophagy promoted a pro-inflammatory response to significantly increase TNF-α and IL-6 production. Taken together, our results define a novel role for miR-146a as a negative regulator of DENV-induced autophagy and identify TRAF6 as a key target of this microRNA in modulating the DENV-autophagy interaction.
Literature
1.
4.
go back to reference Huang J, Li Y, Qi Y, Zhang Y, Zhang L, Wang Z, Zhang X, Gui L (2014) Coordinated regulation of autophagy and apoptosis determines endothelial cell fate during Dengue virus type 2 infection. Mol Cell Biochem 397:157–165. doi:10.1007/s11010-014-2183-3 CrossRefPubMed Huang J, Li Y, Qi Y, Zhang Y, Zhang L, Wang Z, Zhang X, Gui L (2014) Coordinated regulation of autophagy and apoptosis determines endothelial cell fate during Dengue virus type 2 infection. Mol Cell Biochem 397:157–165. doi:10.​1007/​s11010-014-2183-3 CrossRefPubMed
6.
go back to reference Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477CrossRefPubMed Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477CrossRefPubMed
7.
go back to reference Ma Y, Galluzzi L, Zitvogel L, Kroemer G (2013) Autophagy and cellular immune responses. Immunity 39:211–227CrossRefPubMed Ma Y, Galluzzi L, Zitvogel L, Kroemer G (2013) Autophagy and cellular immune responses. Immunity 39:211–227CrossRefPubMed
8.
go back to reference Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR, Rubinsztein DC (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90:1383–1435. doi:10.1152/physrev.00030.2009 CrossRefPubMed Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR, Rubinsztein DC (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90:1383–1435. doi:10.​1152/​physrev.​00030.​2009 CrossRefPubMed
9.
go back to reference Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, Klionsky DJ, Ohsumi M, Ohsumi Y (1998) A protein conjugation system essential for autophagy. Nature 395:395–398CrossRefPubMed Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, Klionsky DJ, Ohsumi M, Ohsumi Y (1998) A protein conjugation system essential for autophagy. Nature 395:395–398CrossRefPubMed
13.
go back to reference Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A (2007) Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315:1398–1401CrossRefPubMed Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A (2007) Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315:1398–1401CrossRefPubMed
16.
go back to reference Reggiori F, Monastyrska I, Verheije MH, Cali T, Ulasli M, Bianchi S, Bernasconi R, de Haan CA, Molinari M (2010) Coronaviruses Hijack the LC3-I-positive edemosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe 7:500–508. doi:10.1016/j.chom.2010.05.013 CrossRefPubMed Reggiori F, Monastyrska I, Verheije MH, Cali T, Ulasli M, Bianchi S, Bernasconi R, de Haan CA, Molinari M (2010) Coronaviruses Hijack the LC3-I-positive edemosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe 7:500–508. doi:10.​1016/​j.​chom.​2010.​05.​013 CrossRefPubMed
21.
go back to reference Heaton NS, Perera R, Berger KL, Khadka S, Lacount DJ, Kuhn RJ, Randall G (2010) Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc Natl Acad Sci USA 107:17345–17350. doi:10.1073/pnas.1010811107 CrossRefPubMedPubMedCentral Heaton NS, Perera R, Berger KL, Khadka S, Lacount DJ, Kuhn RJ, Randall G (2010) Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc Natl Acad Sci USA 107:17345–17350. doi:10.​1073/​pnas.​1010811107 CrossRefPubMedPubMedCentral
24.
go back to reference Harris J, Hartman M, Roche C, Zeng SG, O’Shea A, Sharp FA, Lambe EM, Creagh EM, Golenbock DT, Tschopp J, Kornfeld H, Fitzgerald KA, Lavelle EC (2011) Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem 286:9587–9597. doi:10.1074/jbc.M110.202911 CrossRefPubMedPubMedCentral Harris J, Hartman M, Roche C, Zeng SG, O’Shea A, Sharp FA, Lambe EM, Creagh EM, Golenbock DT, Tschopp J, Kornfeld H, Fitzgerald KA, Lavelle EC (2011) Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem 286:9587–9597. doi:10.​1074/​jbc.​M110.​202911 CrossRefPubMedPubMedCentral
25.
go back to reference Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222–230. doi:10.1038/ni.1980 CrossRefPubMed Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222–230. doi:10.​1038/​ni.​1980 CrossRefPubMed
26.
go back to reference Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456:264–268. doi:10.1038/nature07383 CrossRefPubMed Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456:264–268. doi:10.​1038/​nature07383 CrossRefPubMed
28.
go back to reference Li YY, Ishihara S, Aziz MM, Oka A, Kusunoki R, Tada Y, Yuki T, Amano Y, Ansary MU, Kinoshita Y (2011) Autophagy is required for toll-like receptor-mediated interleukin-8 production in intestinal epithelial cells. Int J Mol Med 27:337–344. doi:10.3892/ijmm.2011.596 PubMed Li YY, Ishihara S, Aziz MM, Oka A, Kusunoki R, Tada Y, Yuki T, Amano Y, Ansary MU, Kinoshita Y (2011) Autophagy is required for toll-like receptor-mediated interleukin-8 production in intestinal epithelial cells. Int J Mol Med 27:337–344. doi:10.​3892/​ijmm.​2011.​596 PubMed
30.
31.
go back to reference Zhu H, Wu H, Liu X, Li B, Chen Y, Ren X, Liu CG, Yang JM (2009) Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells. Autophagy 5:816–823CrossRefPubMedPubMedCentral Zhu H, Wu H, Liu X, Li B, Chen Y, Ren X, Liu CG, Yang JM (2009) Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells. Autophagy 5:816–823CrossRefPubMedPubMedCentral
33.
go back to reference Yang K, Wu M, Li M, Li D, Peng A, Nie X, Sun M, Wang J, Wu Y, Deng Q, Zhu M, Chen K, Yuan J, Huang X (2014) miR-155 suppresses bacterial clearance in pseudomonas aeruginosa-induced keratitis by targeting RHEB. J Infect Dis 210:89–98CrossRefPubMed Yang K, Wu M, Li M, Li D, Peng A, Nie X, Sun M, Wang J, Wu Y, Deng Q, Zhu M, Chen K, Yuan J, Huang X (2014) miR-155 suppresses bacterial clearance in pseudomonas aeruginosa-induced keratitis by targeting RHEB. J Infect Dis 210:89–98CrossRefPubMed
36.
go back to reference Ge YY, Shi Q, Zheng ZY, Gong J, Zeng C, Yang J, Zhuang SM (2014) MicroRNA-100 promotes the autophagy of hepatocellular carcinoma cells by inhibiting the expression of mTOR and IGF-1R. Oncotarget 5:6218–6228CrossRefPubMedPubMedCentral Ge YY, Shi Q, Zheng ZY, Gong J, Zeng C, Yang J, Zhuang SM (2014) MicroRNA-100 promotes the autophagy of hepatocellular carcinoma cells by inhibiting the expression of mTOR and IGF-1R. Oncotarget 5:6218–6228CrossRefPubMedPubMedCentral
38.
go back to reference Reed LJ, Muench H (1938) A simple method of estimating fifty percent endpoints. Am J Hyg 27:493–497 Reed LJ, Muench H (1938) A simple method of estimating fifty percent endpoints. Am J Hyg 27:493–497
39.
go back to reference Maul A (1991) Aspects statistiques des methodes de quantification en virologie. In: Virologie des milieux hydriques Tec & Doc-Lavoisier, pp 143–171 Maul A (1991) Aspects statistiques des methodes de quantification en virologie. In: Virologie des milieux hydriques Tec & Doc-Lavoisier, pp 143–171
40.
go back to reference Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, Bordi M, Gretzmeier C, Dengjel J, Piacentini M, Fimia GM, Cecconi F (2013) mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol 15:406–416. doi:10.1038/ncb2708 CrossRefPubMed Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, Bordi M, Gretzmeier C, Dengjel J, Piacentini M, Fimia GM, Cecconi F (2013) mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol 15:406–416. doi:10.​1038/​ncb2708 CrossRefPubMed
42.
go back to reference Ambjørn M, Ejlerskov P, Liu Y, Lees M, Jäättelä M, Issazadeh-Navikas S (2013) IFNB1/interferon-beta-induced autophagy in MCF-7 breast cancer cells counteracts its proapoptotic function. Autophagy 9:287–302CrossRefPubMedPubMedCentral Ambjørn M, Ejlerskov P, Liu Y, Lees M, Jäättelä M, Issazadeh-Navikas S (2013) IFNB1/interferon-beta-induced autophagy in MCF-7 breast cancer cells counteracts its proapoptotic function. Autophagy 9:287–302CrossRefPubMedPubMedCentral
44.
go back to reference Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103:12481–12486CrossRefPubMedPubMedCentral Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103:12481–12486CrossRefPubMedPubMedCentral
46.
go back to reference Wang PH, Wan DH, Gu ZH, Deng XX, Weng SP, Yu XQ, He JG (2008) Litopenaeus vannamei tumor necrosis factor receptor-associated factor 6 (TRAF6) responds to Vibrio alginolyticus and white spot syndrome virus (WSSV) infection and activates antimicrobial peptide genes. Dev Comp Immunol 35:105–114. doi:10.1016/j.dci.2010.08.013 CrossRef Wang PH, Wan DH, Gu ZH, Deng XX, Weng SP, Yu XQ, He JG (2008) Litopenaeus vannamei tumor necrosis factor receptor-associated factor 6 (TRAF6) responds to Vibrio alginolyticus and white spot syndrome virus (WSSV) infection and activates antimicrobial peptide genes. Dev Comp Immunol 35:105–114. doi:10.​1016/​j.​dci.​2010.​08.​013 CrossRef
49.
go back to reference Chen CL, Lin CF, Wan SW, Wei LS, Chen MC, Yeh TM, Liu HS, Anderson R, Lin YS (2013) Anti-dengue virus nonstructural protein 1 antibodies cause NO-mediated endothelial cell apoptosis via ceramide-regulated glycogen synthase kinase-3β and NF-κB activation. J Immunol 191:1744–1752. doi:10.4049/jimmunol.1201976 CrossRefPubMed Chen CL, Lin CF, Wan SW, Wei LS, Chen MC, Yeh TM, Liu HS, Anderson R, Lin YS (2013) Anti-dengue virus nonstructural protein 1 antibodies cause NO-mediated endothelial cell apoptosis via ceramide-regulated glycogen synthase kinase-3β and NF-κB activation. J Immunol 191:1744–1752. doi:10.​4049/​jimmunol.​1201976 CrossRefPubMed
50.
go back to reference Clyde K, Kyle JL, Harris E (2006) Recent advances in deciphering viral and host determinants of dengue virus replication and pathogenesis. J Virol 80:11418–11431CrossRefPubMedPubMedCentral Clyde K, Kyle JL, Harris E (2006) Recent advances in deciphering viral and host determinants of dengue virus replication and pathogenesis. J Virol 80:11418–11431CrossRefPubMedPubMedCentral
51.
go back to reference Rattanaburee T, Junking M, Panya A, Sawasdee N, Songprakhon P, Suttitheptumrong A, Limjindaporn T, Haegeman G, Yenchitsomanus PT (2015) Inhibition of dengue virus production and cytokine/chemokine expression by ribavirin and compound A. Antiviral Res 124:83–92. doi:10.1016/j.antiviral.2015.10.005 CrossRefPubMed Rattanaburee T, Junking M, Panya A, Sawasdee N, Songprakhon P, Suttitheptumrong A, Limjindaporn T, Haegeman G, Yenchitsomanus PT (2015) Inhibition of dengue virus production and cytokine/chemokine expression by ribavirin and compound A. Antiviral Res 124:83–92. doi:10.​1016/​j.​antiviral.​2015.​10.​005 CrossRefPubMed
54.
go back to reference Huang KJ, Yang YC, Lin YS, Huang JH, Liu HS, Yeh TM, Chen SH, Liu CC, Lei HY (2006) The dual-specific binding of dengue virus and target cells for the antibody-dependent enhancement of dengue virus infection. J Immunol 176:2825–2832CrossRefPubMed Huang KJ, Yang YC, Lin YS, Huang JH, Liu HS, Yeh TM, Chen SH, Liu CC, Lei HY (2006) The dual-specific binding of dengue virus and target cells for the antibody-dependent enhancement of dengue virus infection. J Immunol 176:2825–2832CrossRefPubMed
55.
go back to reference Wati S, Li P, Burrell CJ, Carr JM (2007) Dengue virus (DV) replication in monocyte-derived macrophages is not affected by tumor necrosis factor alpha (TNF-α), and DV infection induces altered responsiveness to TNF-α stimulation. J Virol 81:10161–10171CrossRefPubMedPubMedCentral Wati S, Li P, Burrell CJ, Carr JM (2007) Dengue virus (DV) replication in monocyte-derived macrophages is not affected by tumor necrosis factor alpha (TNF-α), and DV infection induces altered responsiveness to TNF-α stimulation. J Virol 81:10161–10171CrossRefPubMedPubMedCentral
56.
go back to reference Palmer DR, Sun P, Celluzzi C, Bisbing J, Pang S, Sun W, Marovich MA, Burgess T (2005) Differential effects of dengue virus on infected and bystander dendritic cells. J Virol 79:2432–2439CrossRefPubMedPubMedCentral Palmer DR, Sun P, Celluzzi C, Bisbing J, Pang S, Sun W, Marovich MA, Burgess T (2005) Differential effects of dengue virus on infected and bystander dendritic cells. J Virol 79:2432–2439CrossRefPubMedPubMedCentral
Metadata
Title
miR-146a Inhibits dengue-virus-induced autophagy by targeting TRAF6
Authors
Jieying Pu
Siyu Wu
Heping Xie
Yuye Li
Zhicong Yang
Xinwei Wu
Xi Huang
Publication date
01-12-2017
Publisher
Springer Vienna
Published in
Archives of Virology / Issue 12/2017
Print ISSN: 0304-8608
Electronic ISSN: 1432-8798
DOI
https://doi.org/10.1007/s00705-017-3516-9

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