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Herpesvirus infection induces NF-\u03baB signaling through multiple viral and host inputs, yet how this response is terminated during productive infection remains unclear. Here, we identify a host-regulated timing mechanism that limits infection-associated NF-\u03baB signaling during human herpesvirus 6A (HHV-6A) infection. The HHV-6A tegument protein U14 has the intrinsic capacity to induce NF-\u03baB signaling and contributes to infection-associated NF-\u03baB responses. The nuclear adaptor PDLIM2 associates with U14 and couples proteasome-dependent U14 turnover to phospho-p65 (Ser536) downregulation and NF-\u03baB termination. CRISPRi-mediated PDLIM2 knockdown prolonged phospho-p65 (Ser536) signaling and nuclear U14 accumulation, enhanced antiviral and DNA damage-associated programs, increased \u03b3H2AX-marked nuclear stress, and reduced extracellular HHV-6A genome copies. Conversely, U14 knockdown attenuated viral gene expression, extracellular viral genome accumulation, and NF-\u03baB-linked inflammatory gene induction. Collectively, these findings define the U14\u2013PDLIM2 axis as a host-regulated mechanism that coordinates NF-\u03baB termination with control of nuclear stress to support productive HHV-6A infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014576","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:37:41Z","timestamp":1790185061000},"page":"e1014576","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Host-directed clearance of nuclear tegument U14 terminates NF-\u03baB signaling and supports HHV-6A replication"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4911-2464","authenticated-orcid":true,"given":"Khoir","family":"Amaliin","sequence":"first","affiliation":[{"name":"Graduate School of Biomedical and Health Sciences, Hiroshima University","place":["Hiroshima, Japan"],"department":["Department of 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