title: HCV-induced miR-21 contributes to evasion of host immune system by targeting MyD88 and IRAK1.
abstract: Upon recognition of viral components by pattern recognition receptors, such as the toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like helicases, cells are activated to produce type I interferon (IFN) and proinflammatory cytokines. These pathways are tightly regulated by the host to prevent an inappropriate cellular response, but viruses can modulate these pathways to proliferate and spread. In this study, we revealed a novel mechanism in which hepatitis C virus (HCV) evades the immune surveillance system to proliferate by activating microRNA-21 (miR-21). We demonstrated that HCV infection upregulates miR-21, which in turn suppresses HCV-triggered type I IFN production, thus promoting HCV replication. Furthermore, we demonstrated that miR-21 targets two important factors in the TLR signaling pathway, myeloid differentiation factor 88 (MyD88) and interleukin-1 receptor-associated kinase 1 (IRAK1), which are involved in HCV-induced type I IFN production. HCV-mediated activation of miR-21 expression requires viral proteins and several signaling components. Moreover, we identified a transcription factor, activating protein-1 (AP-1), which is partly responsible for miR-21 induction in response to HCV infection through PKCε/JNK/c-Jun and PKCα/ERK/c-Fos cascades. Taken together, our results indicate that miR-21 is upregulated during HCV infection and negatively regulates IFN-α signaling through MyD88 and IRAK1 and may be a potential therapeutic target for antiviral intervention.
authors: State Key Laboratory of Virology, College of Life Sciences, and Chinese-French Liver Disease Research Institute at Zhongnan Hospital, Wuhan University, Wuhan, Hubei, PR China.
authors: Yanni
authors: Y
authors: Chen
authors: Junbo
authors: J
authors: Chen
authors: Hui
authors: H
authors: Wang
authors: Jingjing
authors: J
authors: Shi
authors: Kailang
authors: K
authors: Wu
authors: Shi
authors: S
authors: Liu
authors: Yingle
authors: Y
authors: Liu
authors: Jianguo
authors: J
authors: Wu
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D006526:Hepatitis C / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D016898:Interferon-alpha / Q000096:biosynthesis / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D020365:RNA Helicases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D015854:Up-Regulation; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D048049:Extracellular Signal-Regulated MAP Kinases; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D053592:Interleukin-1 Receptor-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D035683:MicroRNAs; D053594:Myeloid Differentiation Factor 88; D011493:Protein Kinase C; D016760:Proto-Oncogene Proteins c-fos; D020365:RNA Helicases; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases; D051199:Toll-Like Receptor 7; D017361:Viral Nonstructural Proteins; C494232:IRF3 protein, human; C524940:MIRN21 microRNA, human; C507779:MYD88 protein, human; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080106:NS4A protein, flavivirus; C096041:NS5 protein, flavivirus; C470409:TICAM1 protein, human; C495348:TLR7 protein, human; C507768:IRAK1 protein, human
references: Nat Rev Immunol. 2008 Feb;8(2):120-30
references: 18204468
references: N Engl J Med. 2001 Jul 5;345(1):41-52
references: 11439948
references: Nature. 2005 Dec 1;438(7068):685-9
references: 16258535
references: Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1828-33
references: 16446426
references: J Immunol. 2003 Jan 1;170(1):508-19
references: 12496438
references: Gastroenterology. 2006 Jun;130(7):2113-29
references: 16762633
references: Immunity. 2007 Feb;26(2):133-7
references: 17307699
references: FASEB J. 2007 May;21(7):1586-96
references: 17267381
references: Arch Virol. 1998;143(12):2493-503
references: 9930205
references: Immunity. 2007 Dec;27(6):847-59
references: 18055230
references: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13944-9
references: 16166262
references: Mol Cell Biol. 2004 Jan;24(1):192-9
references: 14673155
references: Nat Immunol. 2010 Feb;11(2):141-7
references: 19946272
references: Gut. 2006 Oct;55(10):1475-83
references: 16527836
references: Nat Biotechnol. 2005 Apr;23(4):457-62
references: 15778705
references: J Virol. 2003 Apr;77(7):3898-912
references: 12634350
references: Annu Rev Immunol. 2003;21:335-76
references: 12524386
references: Cell. 2003 Apr 4;113(1):25-36
references: 12679032
references: J Leukoc Biol. 2001 Jun;69(6):912-20
references: 11404376
references: Clin Microbiol Rev. 2001 Oct;14(4):778-809, table of contents
references: 11585785
references: Science. 2007 Apr 27;316(5824):604-8
references: 17463289
references: Clin Cancer Res. 2008 Jan 15;14(2):419-27
references: 18223217
references: Hepatology. 2003 May;37(5):975-8
references: 12717377
references: Hepatology. 2003 Dec;38(6):1458-67
references: 14647057
references: BMC Genomics. 2009 Aug 11;10:373
references: 19671175
references: Nat Rev Immunol. 2002 Sep;2(9):675-87
references: 12209136
references: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2992-7
references: 15710891
references: J Virol. 2006 Feb;80(4):1734-41
references: 16439530
references: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2986-91
references: 15710892
references: Sci STKE. 2007 Jan 02;2007(367):re1
references: 17200520
references: Virology. 2008 Feb 5;371(1):61-70
references: 17964630
references: J Immunol. 2006 Mar 15;176(6):3796-803
references: 16517750
references: Virology. 2010 Mar 1;398(1):57-67
references: 20006370
references: J Infect Dis. 2010 Jul 1;202(1):125-35
references: 20486857
references: Nat Rev Immunol. 2007 Oct;7(10):753-66
references: 17893693
references: Gastroenterology. 2007 Aug;133(2):647-58
references: 17681183
references: J Virol. 2009 Jul;83(13):6757-68
references: 19369349
references: Mol Cell Biol. 2004 Apr;24(7):2614-26
references: 15024053
references: Nucleic Acids Res. 2005 Mar 01;33(4):1290-7
references: 15741182
references: FASEB J. 2011 Dec;25(12):4511-21
references: 21903935
references: J Immunol. 2010 Jun 15;184(12):6773-81
references: 20483747
references: Science. 2005 Jul 22;309(5734):623-6
references: 15947137
references: J Virol. 2005 May;79(9):5507-15
references: 15827165
references: Gene. 1996 Dec 5;182(1-2):203-11
references: 8982089
references: Nature. 2008 Sep 4;455(7209):58-63
references: 18668040
references: Cell. 2006 Feb 24;124(4):783-801
references: 16497588
references: Hepatology. 1991 Aug;14(2):381-8
references: 1650328
references: World J Gastroenterol. 2007 Sep 28;13(36):4818-23
references: 17828812
references: Hepatology. 2012 Jul;56(1):57-66
references: 22318991
references: J Virol. 2001 Sep;75(18):8516-23
references: 11507197
references: J Virol. 2007 Sep;81(17):8953-66
references: 17567694
references: FEBS Lett. 2005 Oct 31;579(26):5911-22
references: 16111679
references: Biochimie. 2007 Jun-Jul;89(6-7):878-83
references: 17561326
references: Nature. 2005 Jun 16;435(7044):974-8
references: 15944714
references: J Mol Biol. 2008 May 2;378(3):492-504
references: 18384814
references: Nat Immunol. 2003 Feb;4(2):161-7
references: 12539043
references: Nat Genet. 2003 Mar;33(3):388-91
references: 12590259
references: Hepatology. 2002 Jan;35(1):199-208
references: 11786977
references: Front Biosci. 2000 Apr 01;5:D406-23
references: 10762593
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1604-9
references: 17242365
references: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11555-7
references: 12192094
references: Biomed Pharmacother. 1998;52(9):386-90
references: 9856285
references: J Virol. 2010 Aug;84(16):8051-61
references: 20519382
references: Nat Rev Immunol. 2005 Jun;5(6):446-58
references: 15928677
references: Nat Immunol. 2008 Aug;9(8):839-45
references: 18645592
references: J Biol Chem. 2010 Jun 25;285(26):20281-90
references: 20404348
references: Front Biosci. 1998 Nov 01;3:D1134-47
references: 9792904
references: Nature. 2005 Apr 7;434(7034):772-7
references: 15800576
references: Cancer Res. 2005 Jul 15;65(14):6029-33
references: 16024602
references: Cell. 1991 Apr 19;65(2):271-80
references: 1849798
references: Nat Genet. 2006 Feb;38(2):228-33
references: 16380711
references: J Immunol. 2009 Aug 1;183(3):2150-8
references: 19596990
references: Science. 1989 Apr 21;244(4902):359-62
references: 2523562
references: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12884-9
references: 17616579
references: J Virol. 2003 May;77(9):5487-92
references: 12692249