Host-directed clearance of nuclear tegument U14 terminates NF-κB signaling and supports HHV-6A replication
- 1Department of Virology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- 2Division of Clinical Virology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- 3Department of Microbiology and Immunology, Gifu Pharmaceutical University, Gifu, Japan
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.
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BibTeX
@article{amaliin2026hostdirected,
title = {{Host-directed clearance of nuclear tegument U14 terminates NF-κB signaling and supports HHV-6A replication}},
author = {Khoir Amaliin and Mansaku Hirai and Salma Aktar and Tetsuo Koshizuka and Yasuko Mori and Jun Arii},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014576},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014576},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Host-directed clearance of nuclear tegument U14 terminates NF-κB signaling and supports HHV-6A replication
AU - Khoir Amaliin
AU - Mansaku Hirai
AU - Salma Aktar
AU - Tetsuo Koshizuka
AU - Yasuko Mori
AU - Jun Arii
PY - 2026
DA - 2026/09/23
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014576
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014576
AB - 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.
SN - 1553-7374
ER -