{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:30:32Z","timestamp":1790829032070,"version":"4.1.0"},"reference-count":59,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2016,5,15]],"date-time":"2016-05-15T00:00:00Z","timestamp":1463270400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81201298"],"award-info":[{"award-number":["81201298"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81471953"],"award-info":[{"award-number":["81471953"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2016,5,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>The NF-\u03baB signaling network, which is an ancient signaling pathway, plays a pivotal role in innate immunity and constitutes a first line of defense against invading pathogens, including viruses. However, numerous viruses possess evolved strategies to antagonize the activation of the NF-\u03baB signaling pathway. Our previous study demonstrated that the nonstructural protein 2C of enterovirus 71 (EV71), which is the major pathogen of hand, foot, and mouth disease, inhibits tumor necrosis factor alpha (TNF-\u03b1)-mediated activation of NF-\u03baB by suppressing I\u03baB kinase \u03b2 (IKK\u03b2) phosphorylation. Nevertheless, the mechanism underlying the inhibition of IKK\u03b2 phosphorylation by EV71 2C remains largely elusive. We demonstrate that EV71 2C interacts with all isoforms of the protein phosphatase 1 (PP1) catalytic subunit (the PP1\u03b1, PP1\u03b2, and PP1\u03b3 isoforms) through PP1-docking motifs. EV71 2C has no influence on the subcellular localization of PP1. In addition, the PP1-binding-deficient EV71 2C mutant 3E3L nearly completely lost the ability to suppress IKK\u03b2 phosphorylation and NF-\u03baB activation was markedly restored in the mutant, thereby indicating that PP1 binding is efficient for EV71 2C-mediated inhibition of IKK\u03b2 phosphorylation and NF-\u03baB activation. We further demonstrate that 2C forms a complex with PP1 and IKK\u03b2 to dephosphorylate IKK\u03b2. Notably, we reveal that other human enteroviruses, including poliovirus (PV), coxsackie A virus 16 (CVA16), and coxsackie B virus 3 (CVB3), use 2C proteins to recruit PP1, leading to the inhibition of IKK\u03b2 phosphorylation. Our findings indicate that enteroviruses exploit a novel mechanism to inhibit IKK\u03b2 phosphorylation by recruiting PP1 and IKK\u03b2 to form a complex through 2C proteins, which ultimately results in the inhibition of the NF-\u03baB signaling pathway.<\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            The innate antiviral immunity system performs an essential function in recognizing and eliminating invading viruses. Enteroviruses include a number of important human pathogens, including poliovirus (PV), EV71, and coxsackieviruses (CVs). As 2C is the most conserved and complex nonstructural protein of enteroviruses, its biological function is largely unclear, whereas the 2A and 3C proteinases of enteroviruses are well characterized. We reveal that EV71 2C forms a complex with PP1 and IKK\u03b2 to maintain IKK\u03b2 in an unphosphorylated and inactive state, resulting in the inactivation of the TNF-\u03b1-mediated NF-\u03baB signaling pathway. We provide evidence that the 2C proteins of the enteroviruses PV, CVA16, and CVB3 suppress IKK\u03b2 phosphorylation through the same mechanism involving PP1. We demonstrate that enteroviruses exploit a novel mechanism involving PP1 to regulate innate antiviral immunity, and our findings may be particularly important for understanding the pathogenicity of enteroviruses.\n          <\/jats:p>","DOI":"10.1128\/jvi.03021-15","type":"journal-article","created":{"date-parts":[[2016,3,10]],"date-time":"2016-03-10T03:39:22Z","timestamp":1457581162000},"page":"5141-5151","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":52,"title":["2C Proteins of Enteroviruses Suppress IKK\u03b2 Phosphorylation by Recruiting Protein Phosphatase 1"],"prefix":"10.1128","volume":"90","author":[{"given":"Qian","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Zheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenfeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingshi","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Meng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianliang","family":"Ke","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinxue","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanzhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/129.3.304"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3402\/ehtj.v6i0.19780"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2014.03.007"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(10)70194-8"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2002.tb00601.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1101\/SQB.1989.054.01.003"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2014.05.004"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203219"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.18.1.621"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2013.05.007"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01360-06"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2008.119"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001311"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2012.01.008"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0606019103"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00447-11"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01855-12"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02491-09"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003231"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063431"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100285"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M102615200"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-7-85"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s15010-012-0244-7"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12250-015-3610-7"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02090-13"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2015.08.007"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2010.03.002"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2012.08547.x"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M503673200"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.556647"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.8.1876"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.10.006"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1600"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/embr.201337983"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209934"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2012.01107.x"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjv041"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/2049-632X.12210"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep14302"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02373-10"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2013.04.008"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.11.018"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.06.007"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.06.008"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.06.013"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2007.11.082"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01467-07"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.21.10409-10420.2001"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/12.18.7251"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.062497-0"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038035"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M611145200"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005067"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-1702(98)00016-1"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1995.1185"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00013.2003"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.115.2.241"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01027-10"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.03021-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.03021-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T14:05:08Z","timestamp":1646489108000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.03021-15"}},"subtitle":[],"editor":[{"given":"S.","family":"L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2016,5,15]]},"references-count":59,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2016,5,15]]}},"alternative-id":["10.1128\/JVI.03021-15"],"URL":"https:\/\/doi.org\/10.1128\/jvi.03021-15","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,15]]},"assertion":[{"value":"2015-12-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-03-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-04-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}