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In this study, we demonstrate that black carp TANK (bcTANK) interacts with bcIKK\u03b5 and significantly enhances its activation of bcIRF3 and bcIRF7, leading to the improved antiviral activity against spring viremia of carp virus (SVCV). Mechanistically, bcTANK recruits deubiquitinase bcUSP46 to bcIKK\u03b5 and leads to a reduction in polyubiquitination of and a concurrent increase in phosphorylation of bcIKK\u03b5, which suggests the activation status of this molecule. Site-directed mutagenesis revealed that lysine residues K418 and K545 of bcIKK\u03b5 are critical for bcIKK\u03b5-mediated IFN production. Furthermore, we identified the SVCV phosphoprotein (P) as a viral antagonist of bcTANK\/bcIKK\u03b5\/bcIRF cascade. The SVCV P protein interacts with bcIKK\u03b5, promotes its polyubiquitination, attenuates its phosphorylation and disrupts its interaction with bcTANK, bcUSP46, bcIRF3, and bcIRF7, thereby facilitating viral replication. Thus, our findings reveal a novel positive regulation of IKK\u03b5 by TANK.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014412","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T17:42:42Z","timestamp":1783705362000},"page":"e1014412","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["TANK potentiates antiviral innate immunity by recruiting deubiquitinase USP46 to activate IKK\u03b5"],"prefix":"10.1371","volume":"22","author":[{"given":"Zhenghao","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaji","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8893-3689","authenticated-orcid":true,"given":"Hao","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"issue":"12","key":"ppat.1014412.ref001","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.molimm.2003.10.005","article-title":"Innate 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