{ "abstract": "Innate immune and cellular stress responses triggered by infection must be transient and tightly controlled to restrain pathogens without harming the host. Herpesvirus infection induces NF-κB 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-κB signaling during human herpesvirus 6A (HHV-6A) infection. The HHV-6A tegument protein U14 has the intrinsic capacity to induce NF-κB signaling and contributes to infection-associated NF-κB responses. The nuclear adaptor PDLIM2 associates with U14 and couples proteasome-dependent U14 turnover to phospho-p65 (Ser536) downregulation and NF-κB termination. CRISPRi-mediated PDLIM2 knockdown prolonged phospho-p65 (Ser536) signaling and nuclear U14 accumulation, enhanced antiviral and DNA damage-associated programs, increased γH2AX-marked nuclear stress, and reduced extracellular HHV-6A genome copies. Conversely, U14 knockdown attenuated viral gene expression, extracellular viral genome accumulation, and NF-κB-linked inflammatory gene induction. Collectively, these findings define the U14–PDLIM2 axis as a host-regulated mechanism that coordinates NF-κB termination with control of nuclear stress to support productive HHV-6A infection. Author summary: Herpesviruses package viral proteins within the virus particle and deliver them into cells at the moment of entry. Some of these proteins rapidly reach the nucleus and can contribute to NF-κB–dependent host responses. These early signals can help initiate infection, but they must be shut off before they become harmful to the infected cell. In this study, we asked how infection-associated nuclear signals are switched off at the right time. We found that, during human herpesvirus 6A (HHV-6A) infection, the viral tegument protein U14 has the capacity to induce NF-κB signaling and contributes to NF-κB–linked responses. We also found that the host nuclear adaptor PDLIM2 associates with U14 and helps terminate this signal by promoting phospho-p65 (Ser536) downregulation and U14 turnover through a proteasome-dependent process. This timed regulation limits ATM-linked nuclear stress and supports viral gene expression and extracellular viral genome accumulation. Upon PDLIM2 knockdown, antiviral and DNA damage-associated programs increase, cellular fitness declines, and extracellular viral genome copies decrease. These findings reveal a host-regulated timing mechanism that coordinates NF-κB shutdown with U14 turnover to support productive HHV-6A infection.", "abstract_shown": true, "affiliations": [ "Department of Virology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan", "Division of Clinical Virology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan", "Department of Microbiology and Immunology, Gifu Pharmaceutical University, Gifu, Japan" ], "article_type": "Research Article", "arxiv": null, "author_total": 6, "authors": [ { "affs": [ 0 ], "name": "Khoir Amaliin" }, { "affs": [ 1 ], "name": "Mansaku Hirai" }, { "affs": [ 2 ], "name": "Salma Aktar" }, { "name": "Tetsuo Koshizuka" }, { "name": "Yasuko Mori" }, { "name": "Jun Arii" } ], "bibtex": "https://research.draconitic.com/paper/cpq767x3tpwmf.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014576", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014576", "id": "cpq767x3tpwmf", "issns": [ "1553-7374" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014576", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1306|NF-κB Signaling Pathways" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/DNA/DNA damage" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/DNA-binding proteins/Transcription factors" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Regulatory proteins/Transcription factors" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/Genomic signal processing" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/Signaling cascades/Stress signaling cascade" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Mechanisms of signal transduction/Signal termination" ], [ "plos", "/Biology and life sciences/Genetics/DNA/DNA damage" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Gene regulation/Transcription factors" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral structure/Tegument proteins" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Molecular probe techniques/Immunoblotting" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Transfection" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Molecular probe techniques/Immunoblotting" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Transfection" ] ], "openalex": "W7214114943", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014576&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-23", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/cpq767x3tpwmf.ris", "sources": [ { "first_seen": "2026-10-30T12:17:43Z", "native_id": "10.1371/journal.ppat.1014576", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014576" } ], "subjects": [ { "field": "biochemistry", "origin": "plos:gene expression", "subfield": "molecular-biology" }, { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" } ], "title": "Host-directed clearance of nuclear tegument U14 terminates NF-κB signaling and supports HHV-6A replication", "title_text": "Host-directed clearance of nuclear tegument U14 terminates NF-κB signaling and supports HHV-6A replication", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:43Z", "url": "https://research.draconitic.com/paper/cpq767x3tpwmf", "venue": "PLOS Pathogens", "versions": [] }