title: Enterovirus 71 protease 2Apro targets MAVS to inhibit anti-viral type I interferon responses.
abstract: Enterovirus 71 (EV71) is the major causative pathogen of hand, foot, and mouth disease (HFMD). Its pathogenicity is not fully understood, but innate immune evasion is likely a key factor. Strategies to circumvent the initiation and effector phases of anti-viral innate immunity are well known; less well known is whether EV71 evades the signal transduction phase regulated by a sophisticated interplay of cellular and viral proteins. Here, we show that EV71 inhibits anti-viral type I interferon (IFN) responses by targeting the mitochondrial anti-viral signaling (MAVS) protein--a unique adaptor molecule activated upon retinoic acid induced gene-I (RIG-I) and melanoma differentiation associated gene (MDA-5) viral recognition receptor signaling--upstream of type I interferon production. MAVS was cleaved and released from mitochondria during EV71 infection. An in vitro cleavage assay demonstrated that the viral 2A protease (2A(pro)), but not the mutant 2A(pro) (2A(pro)-110) containing an inactivated catalytic site, cleaved MAVS. The Protease-Glo assay revealed that MAVS was cleaved at 3 residues between the proline-rich and transmembrane domains, and the resulting fragmentation effectively inactivated downstream signaling. In addition to MAVS cleavage, we found that EV71 infection also induced morphologic and functional changes to the mitochondria. The EV71 structural protein VP1 was detected on purified mitochondria, suggesting not only a novel role for mitochondria in the EV71 replication cycle but also an explanation of how EV71-derived 2A(pro) could approach MAVS. Taken together, our findings reveal a novel strategy employed by EV71 to escape host anti-viral innate immunity that complements the known EV71-mediated immune-evasion mechanisms.
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Xueyan
authors.initials: X
authors.lastname: Xi
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Lei
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Sheng
authors.initials: S
authors.lastname: Cui
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D029821:Enterovirus A, Human / Q000187:drug effects / Q000201:enzymology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D012327:RNA Virus Infections; D012208:Rhabdomyosarcoma; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D007370:Interferon Type I; D011480:Protease Inhibitors; D003546:Cysteine Endopeptidases
references.citation: J Infect Dis. 1974 Mar;129(3):304-9
references.pmid: 4361245
references.citation: J Virol Methods. 2009 Mar;156(1-2):129-37
references.pmid: 19095010
references.citation: Biochem Biophys Res Commun. 1997 Jun 27;235(3):562-6
references.pmid: 9207196
references.citation: Mol Cell. 2005 Sep 16;19(6):727-40
references.pmid: 16153868
references.citation: J Mol Biol. 2011 May 6;408(3):449-61
references.pmid: 21396941
references.citation: Cell. 2010 Apr 16;141(2):315-30
references.pmid: 20403326
references.citation: J Virol. 2007 Jan;81(2):964-76
references.pmid: 17093192
references.citation: PLoS Pathog. 2011 Mar;7(3):e1001311
references.pmid: 21436888
references.citation: Proc Natl Acad Sci U S A. 2009 May 26;106(21):8653-8
references.pmid: 19433799
references.citation: PLoS Pathog. 2009 Sep;5(9):e1000593
references.pmid: 19779565
references.citation: J Biomed Biotechnol. 2011;2011:369648
references.pmid: 21541224
references.citation: J Biomed Sci. 2010 Aug 04;17:65
references.pmid: 20682079
references.citation: J Virol. 2000 Mar;74(6):2840-6
references.pmid: 10684300
references.citation: J Virol. 2007 Apr;81(8):3677-84
references.pmid: 17267501
references.citation: Sheng Wu Gong Cheng Xue Bao. 2005 Mar;21(2):182-6
references.pmid: 16013472
references.citation: Nat Immunol. 2009 Dec;10(12):1300-8
references.pmid: 19881509
references.citation: Immunol Rev. 2009 Jan;227(1):54-65
references.pmid: 19120475
references.citation: J Virol. 1999 Jan;73(1):251-9
references.pmid: 9847328
references.citation: PLoS One. 2008 Apr 02;3(4):e1887
references.pmid: 18382670
references.citation: J Neurosci Methods. 2006 Apr 15;152(1-2):136-43
references.pmid: 16253339
references.citation: J Neurovirol. 2004 Dec;10(6):338-49
references.pmid: 15765805
references.citation: Cell. 2005 Sep 9;122(5):669-82
references.pmid: 16125763
references.citation: Virology. 2009 Oct 25;393(2):311-8
references.pmid: 19733381
references.citation: J Med Virol. 2006 Jun;78(6):780-6
references.pmid: 16628611
references.citation: FEBS Lett. 2000 Sep 1;480(2-3):151-5
references.pmid: 11034318
references.citation: Virology. 2002 Feb 15;293(2):386-95
references.pmid: 11886259
references.citation: Nat Protoc. 2009;4(11):1582-90
references.pmid: 19816421
references.citation: J Virol. 2004 Apr;78(7):3271-8
references.pmid: 15016848
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7253-8
references.pmid: 17438296
references.citation: EMBO Rep. 2010 Feb;11(2):133-8
references.pmid: 20019757
references.citation: J Virol. 2005 Jul;79(13):8014-23
references.pmid: 15956547
references.citation: J Gen Virol. 2002 Jun;83(Pt 6):1367-1376
references.pmid: 12029152
references.citation: J Immunol. 2010 Jun 1;184(11):6249-55
references.pmid: 20483786
references.citation: Biochemistry. 1997 Jun 24;36(25):7802-9
references.pmid: 9201923
references.citation: J Gen Virol. 2005 Dec;86(Pt 12):3263-3269
references.pmid: 16298971
references.citation: J Virol. 1988 Nov;62(11):4407-9
references.pmid: 2845152
references.citation: Sci Signal. 2011 Feb 01;4(158):ra7
references.pmid: 21285412
references.citation: Virology. 1991 Mar;181(1):46-54
references.pmid: 1847268
references.citation: J Virol. 2006 Jun;80(12):6072-83
references.pmid: 16731946
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14590-5
references.pmid: 21844353
references.citation: J Virol. 2012 Apr;86(7):3767-76
references.pmid: 22258259
references.citation: Nat Immunol. 2005 Oct;6(10):981-8
references.pmid: 16127453
references.citation: J Biol Chem. 1992 Nov 5;267(31):22639-44
references.pmid: 1331062
references.citation: Genes Cells. 2001 Apr;6(4):375-88
references.pmid: 11318879
references.citation: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7500-5
references.pmid: 17460044
references.citation: J Virol. 2009 Nov;83(22):11581-7
references.pmid: 19740998
references.citation: Cell Microbiol. 2008 Feb;10(2):437-51
references.pmid: 17961183
references.citation: PLoS One. 2008 Jul 09;3(7):e2585
references.pmid: 18612413
references.citation: J Biol Chem. 2011 Sep 9;286(36):31373-84
references.pmid: 21784861
references.citation: Virology. 2009 Sep 1;391(2):171-6
references.pmid: 19628239
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17717-22
references.pmid: 16301520
references.citation: J Immunol. 2010 Jul 15;185(2):1158-68
references.pmid: 20554965
references.citation: FEMS Microbiol Rev. 2002 Mar;26(1):91-107
references.pmid: 12007645
references.citation: J Virol. 2008 Apr;82(7):3500-8
references.pmid: 18216110
references.citation: J Virol. 2010 Aug;84(16):8051-61
references.pmid: 20519382
references.citation: J Virol. 2009 May;83(9):4412-22
references.pmid: 19211759
references.citation: J Virol. 2001 Dec;75(23):11664-76
references.pmid: 11689648
references.citation: Curr Protoc Cell Biol. 2007 Dec;Chapter 3:Unit 3.27
references.pmid: 18228515
references.citation: J Virol. 2011 Jan;85(2):987-95
references.pmid: 21068253
references.citation: Mol Cell. 2009 Oct 23;36(2):315-25
references.pmid: 19854139
references.citation: Immunol Rev. 2007 Dec;220:214-24
references.pmid: 17979849
references.citation: J Virol. 1999 Apr;73(4):3467-72
references.pmid: 10074204
references.citation: Nat Immunol. 2006 Feb;7(2):131-7
references.pmid: 16424890
references.citation: J Virol. 2011 Sep;85(17):8811-8
references.pmid: 21697485
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):6001-6
references.pmid: 16585524
references.citation: J Gen Virol. 2006 Jul;87(Pt 7):1935-1945
references.pmid: 16760395
references.citation: Nature. 2005 Oct 20;437(7062):1167-72
references.pmid: 16177806
references.citation: J Gen Virol. 1993 Dec;74 ( Pt 12):2645-52
references.pmid: 8277270