{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:08:01Z","timestamp":1790766481652,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T00:00:00Z","timestamp":1577664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State Key Laboratory of Veterinary Biotechnology Foundation","award":["SKLVBP2018002"],"award-info":[{"award-number":["SKLVBP2018002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Feline infectious peritonitis (FIP), caused by virulent feline coronavirus, is the leading infectious cause of death in cats. The type I interferon (type I IFN)-mediated immune responses provide host protection from infectious diseases. Several coronaviruses have been reported to evolve diverse strategies to evade host IFN response. However, whether feline infectious peritonitis virus (FIPV) antagonizes the type I IFN signaling remains unclear. In this study, we demonstrated that FIPV strain DF2 infection not only failed to induce interferon-\u03b2 (IFN-\u03b2) and interferon-stimulated gene (ISG) production, but also inhibited Sendai virus (SEV) or polyinosinic-polycytidylic acid (poly(I:C))-induced IFN-\u03b2 production. Subsequently, we found that one of the non-structural proteins encoded by the FIPV genome, nsp5, interrupted type I IFN signaling in a protease-dependent manner by cleaving the nuclear factor \u03baB (NF-\u03baB) essential modulator (NEMO) at three sites\u2014glutamine132 (Q132), Q205, and Q231. Further investigation revealed that the cleavage products of NEMO lost the ability to activate the IFN-\u03b2 promoter. Mechanistically, the nsp5-mediated NEMO cleavage disrupted the recruitment of the TRAF family member-associated NF-\u03baB activator (TANK) to NEMO, which reduced the phosphorylation of interferon regulatory factor 3 (IRF3), leading to the inhibition of type I IFN production. Our research provides new insights into the mechanism for FIPV to counteract host innate immune response.<\/jats:p>","DOI":"10.3390\/v12010043","type":"journal-article","created":{"date-parts":[[2020,1,3]],"date-time":"2020-01-03T03:28:53Z","timestamp":1578022133000},"page":"43","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Feline Infectious Peritonitis Virus Nsp5 Inhibits Type I Interferon Production by Cleaving NEMO at Multiple Sites"],"prefix":"10.3390","volume":"12","author":[{"given":"Si","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Tian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijie","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtao","family":"Kang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jikai","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiapei","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Yin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoliang","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liandong","family":"Qu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"606","DOI":"10.7589\/0090-3558-42.3.606","article-title":"Factors associated with pathogen seroprevalence and infection in Rocky Mountain cougars","volume":"42","author":"Biek","year":"2006","journal-title":"J. Wildl. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1128\/cdli.3.5.554-562.1996","article-title":"Prevalence of antibodies to feline parvovirus, calicivirus, herpesvirus, coronavirus, and immunodeficiency virus and of feline leukemia virus antigen and the interrelationship of these viral infections in free-ranging lions in east Africa","volume":"3","author":"Fehr","year":"1996","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0378-1135(93)90126-R","article-title":"A review of feline infectious peritonitis virus: Molecular biology, immunopathogenesis, clinical aspects, and vaccination","volume":"36","author":"Olsen","year":"1993","journal-title":"Vet. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1292\/jvms.54.557","article-title":"The prevalence of types I and II feline coronavirus infections in cats","volume":"54","author":"Hohdatsu","year":"1992","journal-title":"J. Vet. Med. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kim, Y., Liu, H., Galasiti Kankanamalage, A.C., Weerasekara, S., Hua, D.H., Groutas, W.C., Chang, K.O., and Pedersen, N.C. (2016). Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005531"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14122","DOI":"10.1128\/JVI.79.22.14122-14130.2005","article-title":"Acquisition of macrophage tropism during the pathogenesis of feline infectious peritonitis is determined by mutations in the feline coronavirus spike protein","volume":"79","author":"Rottier","year":"2005","journal-title":"J. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1099\/vir.0.016485-0","article-title":"Feline infectious peritonitis: Insights into feline coronavirus pathobiogenesis and epidemiology based on genetic analysis of the viral 3c gene","volume":"91","author":"Chang","year":"2010","journal-title":"J. Gen. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"166","DOI":"10.3390\/v1020166","article-title":"Significance of coronavirus mutants in feces and diseased tissues of cats suffering from feline infectious peritonitis","volume":"1","author":"Pedersen","year":"2009","journal-title":"Viruses"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1006\/viro.1998.9045","article-title":"Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses","volume":"243","author":"Vennema","year":"1998","journal-title":"Virology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0378-1135(01)00354-6","article-title":"Deletions in the 7a ORF of feline coronavirus associated with an epidemic of feline infectious peritonitis","volume":"81","author":"Kennedy","year":"2001","journal-title":"Vet. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1128\/JVI.79.2.1036-1044.2005","article-title":"Natural history of a recurrent feline coronavirus infection and the role of cellular immunity in survival and disease","volume":"79","year":"2005","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1177\/1098612X15623824","article-title":"Detection of feline coronavirus spike gene mutations as a tool to diagnose feline infectious peritonitis","volume":"19","author":"Felten","year":"2015","journal-title":"J. Feline Med. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1177\/1098612X18762883","article-title":"Detection of feline coronavirus mutations in paraffin-embedded tissues in cats with feline infectious peritonitis and controls","volume":"21","author":"Sangl","year":"2019","journal-title":"J. Feline Med. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.tvjl.2014.04.017","article-title":"An update on feline infectious peritonitis: Virology and immunopathogenesis","volume":"201","author":"Pedersen","year":"2014","journal-title":"Vet. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.vetmic.2014.10.025","article-title":"Levels of feline infectious peritonitis virus in blood, effusions, and various tissues and the role of lymphopenia in disease outcome following experimental infection","volume":"175","author":"Pedersen","year":"2015","journal-title":"Vet. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vetmic.2003.08.010","article-title":"In vivo cytokine response to experimental feline infectious peritonitis virus infection","volume":"97","author":"Dean","year":"2003","journal-title":"Vet. Microbiol."},{"key":"ref_17","first-page":"1193","article-title":"Effect of feline interferon-omega on the survival time and quality of life of cats with feline infectious peritonitis","volume":"21","author":"Ritz","year":"2007","journal-title":"J. Vet. Intern. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1111\/j.1939-1676.2011.00806.x","article-title":"Randomized, placebo controlled study of the effect of propentofylline on survival time and quality of life of cats with feline infectious peritonitis","volume":"25","author":"Fischer","year":"2011","journal-title":"J. Vet. Intern. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4942","DOI":"10.1128\/JVI.03688-14","article-title":"Broad-spectrum inhibitors against 3C-like proteases of feline coronaviruses and feline caliciviruses","volume":"89","author":"Kim","year":"2015","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1146\/annurev.micro.60.080805.142157","article-title":"Biochemical aspects of coronavirus replication and virus-host interaction","volume":"60","author":"Enjuanes","year":"2006","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.virusres.2006.01.017","article-title":"Nidovirales: Evolving the largest RNA virus genome","volume":"117","author":"Gorbalenya","year":"2006","journal-title":"Virus Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1099\/0022-1317-69-12-2939","article-title":"Coronaviruses: Structure and genome expression","volume":"69","author":"Spaan","year":"1988","journal-title":"J. Gen. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5072","DOI":"10.1016\/j.bmcl.2015.10.023","article-title":"X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design","volume":"25","author":"Therkelsen","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.coviro.2014.06.002","article-title":"Antiviral drugs specific for coronaviruses in preclinical development","volume":"8","author":"Adedeji","year":"2014","journal-title":"Curr. Opin. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1586\/14787210.4.2.291","article-title":"Potential antivirals and antiviral strategies against SARS coronavirus infections","volume":"4","year":"2006","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1146\/annurev-immunol-032713-120156","article-title":"Innate immune sensing and signaling of cytosolic nucleic acids","volume":"32","author":"Wu","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.cell.2005.08.012","article-title":"Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3","volume":"122","author":"Seth","year":"2005","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1126\/science.8197455","article-title":"Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins","volume":"264","author":"Darnell","year":"1994","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/ncb0805-758","article-title":"Ubiquitin signalling in the NF-kappaB pathway","volume":"7","author":"Chen","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"37029","DOI":"10.1074\/jbc.M205069200","article-title":"Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases","volume":"277","author":"Chariot","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"27861","DOI":"10.1074\/jbc.M314278200","article-title":"The trimerization domain of NEMO is composed of the interacting C-terminal CC2 and LZ coiled-coil subdomains","volume":"279","author":"Agou","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/ni1465","article-title":"The NEMO adaptor bridges the nuclear factor-kappaB and interferon regulatory factor signaling pathways","volume":"8","author":"Zhao","year":"2007","journal-title":"Nat. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.virol.2015.12.010","article-title":"Suppression of type I interferon production by porcine epidemic diarrhea virus and degradation of CREB-binding protein by nsp1","volume":"489","author":"Zhang","year":"2016","journal-title":"Virology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s13238-014-0026-3","article-title":"SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex","volume":"5","author":"Chen","year":"2014","journal-title":"Protein Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.mib.2014.05.005","article-title":"To sense or not to sense viral RNA\u2014Essentials of coronavirus innate immune evasion","volume":"20","author":"Kindler","year":"2014","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Menachery, V.D., Gralinski, L.E., Mitchell, H.D., Dinnon, K.H., Leist, S.R., Yount, B.L., Graham, R.L., McAnarney, E.T., Stratton, K.G., and Cockrell, A.S. (2017). Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis. mSphere, 2.","DOI":"10.1128\/mSphere.00346-17"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1099\/vir.0.058743-0","article-title":"ORF7-encoded accessory protein 7a of feline infectious peritonitis virus as a counteragent against IFN-alpha-induced antiviral response","volume":"95","author":"Dedeurwaerder","year":"2014","journal-title":"J. Gen. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.meegid.2015.06.003","article-title":"Assessment of the IFN-beta response to four feline caliciviruses: Infection in CRFK cells","volume":"34","author":"Tian","year":"2015","journal-title":"Infect. Genet. Evol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Tian, J., Liu, Y., Liu, X., Sun, X., Zhang, J., and Qu, L. (2018). Feline Herpesvirus 1 US3 Blocks the Type I Interferon Signal Pathway by Targeting Interferon Regulatory Factor 3 Dimerization in a Kinase-Independent Manner. J. Virol., 92.","DOI":"10.1128\/JVI.00047-18"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1146\/annurev-immunol-032713-120231","article-title":"Interferon-stimulated genes: A complex web of host defenses","volume":"32","author":"Schneider","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1128\/JVI.02514-15","article-title":"Porcine Epidemic Diarrhea Virus 3C-Like Protease Regulates Its Interferon Antagonism by Cleaving NEMO","volume":"90","author":"Wang","year":"2016","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chuck, C.P., Chong, L.T., Chen, C., Chow, H.F., Wan, D.C., and Wong, K.B. (2010). Profiling of substrate specificity of SARS-CoV 3CL. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013197"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Chuck, C.P., Chow, H.F., Wan, D.C., and Wong, K.B. (2011). Profiling of substrate specificities of 3C-like proteases from group 1, 2a, 2b, and 3 coronaviruses. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027228"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.coviro.2011.04.004","article-title":"RIG-I like receptors and their signaling crosstalk in the regulation of antiviral immunity","volume":"1","author":"Ramos","year":"2011","journal-title":"Curr. Opin. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Pearson, M., LaVoy, A., Evans, S., Vilander, A., Webb, C., Graham, B., Musselman, E., LeCureux, J., VandeWoude, S., and Dean, G.A. (2019). Mucosal Immune Response to Feline Enteric Coronavirus Infection. Viruses, 11.","DOI":"10.3390\/v11100906"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.vetmic.2018.04.026","article-title":"The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies","volume":"219","author":"Murphy","year":"2018","journal-title":"Vet. Microbiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8811","DOI":"10.1128\/JVI.00447-11","article-title":"Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3","volume":"85","author":"Lei","year":"2011","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1128\/JVI.01855-12","article-title":"Cleavage of interferon regulatory factor 7 by enterovirus 71 3C suppresses cellular responses","volume":"87","author":"Lei","year":"2013","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27618","DOI":"10.1074\/jbc.M115.660761","article-title":"Encephalomyocarditis Virus 3C Protease Relieves TRAF Family Member-associated NF-kappaB Activator (TANK) Inhibitory Effect on TRAF6-mediated NF-kappaB Signaling through Cleavage of TANK","volume":"290","author":"Huang","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"9311","DOI":"10.1128\/JVI.00722-12","article-title":"Foot-and-mouth disease virus 3C protease cleaves NEMO to impair innate immune signaling","volume":"86","author":"Wang","year":"2012","journal-title":"J. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10252","DOI":"10.1128\/JVI.00869-14","article-title":"Hepatitis A virus 3C protease cleaves NEMO to impair induction of beta interferon","volume":"88","author":"Wang","year":"2014","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10934","DOI":"10.1128\/JVI.01396-14","article-title":"Porcine reproductive and respiratory syndrome virus nonstructural protein 4 antagonizes beta interferon expression by targeting the NF-kappaB essential modulator","volume":"88","author":"Huang","year":"2014","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Qian, S., Fan, W., Liu, T., Wu, M., Zhang, H., Cui, X., Zhou, Y., Hu, J., Wei, S., and Chen, H. (2017). Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage. J. Virol., 91.","DOI":"10.1128\/JVI.00823-17"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/1\/43\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:46:44Z","timestamp":1760190404000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/1\/43"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,30]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["v12010043"],"URL":"https:\/\/doi.org\/10.3390\/v12010043","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,30]]}}}