{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:12:54Z","timestamp":1788959574072,"version":"build-2803163510"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T00:00:00Z","timestamp":1636675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated interleukin-1 beta (IL-1\u03b2) production is one of the crucial responses in innate immunity upon infection with viruses including influenza A virus (IAV) and is modulated by both viral and host cellular proteins. Among host proteins involved, we identified tripartite motif-containing protein 25 (TRIM25) as a positive regulator of porcine NLRP3 inflammasome-mediated IL-1\u03b2 production. TRIM25 achieved this function by enhancing the pro-caspase-1 interaction with apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). The N-terminal RING domain, particularly residues predicted to be critical for the E3 ligase activity of TRIM25, was responsible for this enhancement. However, non-structural protein 1 (NS1) C-terminus of 2009 pandemic IAV interfered with this action by interacting with TRIM25, leading to diminished association between pro-caspase-1 and ASC. These findings demonstrate that TRIM25 promotes the IL-1\u03b2 signaling, while it is repressed by IAV NS1 protein, revealing additional antagonism of the NS1 against host pro-inflammatory responses.<\/jats:p>","DOI":"10.3389\/fmicb.2021.778950","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T13:55:30Z","timestamp":1636725330000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["NLRP3 Inflammasome Activation Enhanced by TRIM25 is Targeted by the NS1 Protein of 2009 Pandemic Influenza A Virus"],"prefix":"10.3389","volume":"12","author":[{"given":"Hong-Su","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kannupriya","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GuanQun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.immuni.2009.02.005","article-title":"The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA","volume":"30","author":"Allen","year":"2009","journal-title":"Immunity"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"2086","DOI":"10.1099\/vir.0.000171","article-title":"The C terminus of NS1 protein of influenza A\/WSN\/1933(H1N1) virus modulates antiviral responses in infected human macrophages and mice","volume":"96","author":"Anastasina","year":"2015","journal-title":"J. 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Immunol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"6909","DOI":"10.1128\/JVI.00081-10","article-title":"Inefficient control of host gene expression by the 2009 pandemic H1N1 influenza A virus NS1 protein","volume":"84","author":"Hale","year":"2010","journal-title":"J. Virol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1002\/cbin.11592","article-title":"E3 ubiquitin ligase TRIM24 deficiency promotes NLRP3\/caspase-1\/IL-1beta-mediated pyroptosis in endometriosis","volume":"45","author":"Hang","year":"2021","journal-title":"Cell Biol. Int."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1038\/nature16959","article-title":"NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux","volume":"530","author":"He","year":"2016","journal-title":"Nature"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"7699","DOI":"10.4049\/jimmunol.1001099","article-title":"Tripartite-motif protein 30 negatively regulates NLRP3 inflammasome activation by modulating reactive oxygen species production","volume":"185","author":"Hu","year":"2010","journal-title":"J. Immunol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1084\/jem.20081667","article-title":"Inflammasome recognition of influenza virus is essential for adaptive immune responses","volume":"206","author":"Ichinohe","year":"2009","journal-title":"J. Exp. 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Immunol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1038\/nature11290","article-title":"Novel role of PKR in inflammasome activation and HMGB1 release","volume":"488","author":"Lu","year":"2012","journal-title":"Nature"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1038\/s41419-019-1491-7","article-title":"HSP70 is a negative regulator of NLRP3 inflammasome activation","volume":"10","author":"Martine","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/j.chom.2017.10.003","article-title":"Nuclear TRIM25 specifically targets influenza virus ribonucleoproteins to block the onset of RNA chain elongation","volume":"22","author":"Meyerson","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"4105","DOI":"10.1128\/JVI.00120-16","article-title":"The RNA- and TRIM25-binding domains of influenza virus NS1 protein are essential for suppression of NLRP3 inflammasome-mediated interleukin-1\u03b2 secretion","volume":"90","author":"Moriyama","year":"2016","journal-title":"J. Virol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"e00022","DOI":"10.1128\/JVI.00022-18","article-title":"NS1 protein of 2009 pandemic influenza A virus inhibits porcine NLRP3 Inflammasome-mediated Interleukin-1 Beta production by suppressing ASC ubiquitination","volume":"92","author":"Park","year":"2018","journal-title":"J. Virol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e1003256","DOI":"10.1371\/journal.ppat.1003256","article-title":"Type I IFN triggers RIG-I\/TLR3\/NLRP3-dependent inflammasome activation in influenza A virus infected cells","volume":"9","author":"Pothlichet","year":"2013","journal-title":"PLoS Pathog."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"779","DOI":"10.3389\/fimmu.2017.00779","article-title":"The C-terminal effector domain of non-structural protein 1 of influenza A virus blocks IFN-\u03b2 production by targeting TNF receptor-associated factor 3","volume":"8","author":"Qian","year":"2017","journal-title":"Front. Immunol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"4794","DOI":"10.1038\/s41467-021-25033-4","article-title":"TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation","volume":"12","author":"Qin","year":"2021","journal-title":"Nat. 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Virol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"8865","DOI":"10.1096\/fj.201802418R","article-title":"Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC","volume":"33","author":"Siu","year":"2019","journal-title":"FASEB J."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"13727","DOI":"10.1038\/ncomms13727","article-title":"The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3","volume":"7","author":"Song","year":"2016","journal-title":"Nat. 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Toxicol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"197647","DOI":"10.1016\/j.virusres.2019.197647","article-title":"Characterization of porcine tripartite motif genes as host restriction factors against PRRSV and PEDV infection","volume":"270","author":"Wei","year":"2019","journal-title":"Virus Res."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"3676","DOI":"10.4049\/jimmunol.1401448","article-title":"The E3 ubiquitin ligase tripartite motif 33 is essential for cytosolic RNA-induced NLRP3 inflammasome activation","volume":"193","author":"Weng","year":"2014","journal-title":"J. Immunol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.4049\/jimmunol.1700175","article-title":"Cutting edge: TRAF6 mediates TLR\/IL-1R Signaling-induced nontranscriptional priming of the NLRP3 Inflammasome","volume":"199","author":"Xing","year":"2017","journal-title":"J. Immunol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.fsi.2016.06.005","article-title":"RING domain is essential for the antiviral activity of TRIM25 from orange spotted grouper","volume":"55","author":"Yang","year":"2016","journal-title":"Fish Shellfish Immunol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e49666","DOI":"10.15252\/embr.201949666","article-title":"EphA2 phosphorylates NLRP3 and inhibits inflammasomes in airway epithelial cells","volume":"21","author":"Zhang","year":"2020","journal-title":"EMBO Rep."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.778950\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T13:55:33Z","timestamp":1636725333000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.778950\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,12]]},"references-count":43,"alternative-id":["10.3389\/fmicb.2021.778950"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.778950","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,12]]},"article-number":"778950"}}