Deubiquitinase USP8 inhibits HIV-1 replication by suppressing Tat-mediated viral transactivation
4 affiliations
- 1Department of Infectious Diseases, Infectious Diseases and Pathogen Biology Center, The First Hospital of Jilin University, Changchun, Jilin, China
- 2Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, Jilin, China
- 3Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
- 4Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
Abstract
Ubiquitin-specific proteases (USPs) modulate diverse virus-host interaction events through deubiquitination; thus, investigating their functional roles and molecular targets facilitates the interpretation of viral pathogenic mechanisms and informs the design of anti-virus strategies. The deubiquitinase USP8 has been reported to antagonize HIV-1 replication by reversing Vif-mediated ubiquitination of the host restriction factor A3G and shielding it from proteasomal degradation. Here, we identify an additional A3G-independent anti-HIV mechanism of USP8. In A3G-negative cells, USP8 exerts a potent inhibitory effect on HIV-1 replication by significantly suppressing viral transcription. Mechanistically, USP8 interacts with the HIV-1 trans-activator Tat through its C-terminal domain and mediates the removal of Tat’s polyubiquitination chains in a manner dependent on USP8 catalytic activity. This disrupts the association between Tat and the HIV-1 LTR transactivation response (TAR) element, thus impairing Tat-mediated viral transactivation. Furthermore, given the essential role of Tat in driving viral gene expression, silencing of USP8 triggers latent HIV-1 reactivation. Collectively, our results, along with previous work, reveal that USP8 acts as a compelling anti-HIV factor that, by regulating both host and viral proteins, ultimately suppresses HIV-1 replication. These results deepen our understanding of USP8-mediated HIV-1 restriction and provide insights for the development of novel anti-HIV therapeutic strategies.
IMPORTANCE: Ubiquitination modification contributes a non-negligible part to the regulation of HIV-1 replication, and the interpretation of key factors involved in this process has significantly benefited our understanding of the virus-host interplay. USP8 is a ubiquitin-specific protease that was recently identified to restrict HIV-1 replication by stabilizing the host restriction factor A3G through reversing the Vif-mediated ubiquitination of A3G. Here, we demonstrate an additional A3G-independent anti-HIV mechanism of USP8. In A3G-negative cells, USP8 directly interacts with and deubiquitinates Tat to cleave its K63-linked ubiquitination, thereby suppressing Tat-mediated HIV-1 trans-activation. The suppression of Tat-driven viral transcription induced by USP8 requires the enzymatic activity of USP8 and is effective in different HIV-1 tropic strains. In addition, the fact that Tat is a novel substrate of USP8 is validated both in cells and by in vitro deubiquitination assays. These findings illustrate the dual regulatory roles of USP8 on both host antiviral factors and viral proteins, expanding our understanding of host-mediated HIV-1 restriction.
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BibTeX
@article{yuan2026deubiquitinase,
title = {{Deubiquitinase USP8 inhibits HIV-1 replication by suppressing Tat-mediated viral transactivation}},
author = {Jinsong Yuan and Weijing Yang and Mingxiu Xu and Haobo Hu and Shuhan Yang and Xiaodong Sun and Wenyan Zhang and Chen Huan},
journal = {Journal of Virology},
year = {2026},
month = sep,
doi = {10.1128/jvi.00598-26},
url = {https://doi.org/10.1128/jvi.00598-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Deubiquitinase USP8 inhibits HIV-1 replication by suppressing Tat-mediated viral transactivation
AU - Jinsong Yuan
AU - Weijing Yang
AU - Mingxiu Xu
AU - Haobo Hu
AU - Shuhan Yang
AU - Xiaodong Sun
AU - Wenyan Zhang
AU - Chen Huan
PY - 2026
DA - 2026/09/28
JO - Journal of Virology
DO - 10.1128/jvi.00598-26
UR - https://doi.org/10.1128/jvi.00598-26
AB - Ubiquitin-specific proteases (USPs) modulate diverse virus-host interaction events through deubiquitination; thus, investigating their functional roles and molecular targets facilitates the interpretation of viral pathogenic mechanisms and informs the design of anti-virus strategies. The deubiquitinase USP8 has been reported to antagonize HIV-1 replication by reversing Vif-mediated ubiquitination of the host restriction factor A3G and shielding it from proteasomal degradation. Here, we identify an additional A3G-independent anti-HIV mechanism of USP8. In A3G-negative cells, USP8 exerts a potent inhibitory effect on HIV-1 replication by significantly suppressing viral transcription. Mechanistically, USP8 interacts with the HIV-1 trans-activator Tat through its C-terminal domain and mediates the removal of Tat’s polyubiquitination chains in a manner dependent on USP8 catalytic activity. This disrupts the association between Tat and the HIV-1 LTR transactivation response (TAR) element, thus impairing Tat-mediated viral transactivation. Furthermore, given the essential role of Tat in driving viral gene expression, silencing of USP8 triggers latent HIV-1 reactivation. Collectively, our results, along with previous work, reveal that USP8 acts as a compelling anti-HIV factor that, by regulating both host and viral proteins, ultimately suppresses HIV-1 replication. These results deepen our understanding of USP8-mediated HIV-1 restriction and provide insights for the development of novel anti-HIV therapeutic strategies. IMPORTANCE: Ubiquitination modification contributes a non-negligible part to the regulation of HIV-1 replication, and the interpretation of key factors involved in this process has significantly benefited our understanding of the virus-host interplay. USP8 is a ubiquitin-specific protease that was recently identified to restrict HIV-1 replication by stabilizing the host restriction factor A3G through reversing the Vif-mediated ubiquitination of A3G. Here, we demonstrate an additional A3G-independent anti-HIV mechanism of USP8. In A3G-negative cells, USP8 directly interacts with and deubiquitinates Tat to cleave its K63-linked ubiquitination, thereby suppressing Tat-mediated HIV-1 trans-activation. The suppression of Tat-driven viral transcription induced by USP8 requires the enzymatic activity of USP8 and is effective in different HIV-1 tropic strains. In addition, the fact that Tat is a novel substrate of USP8 is validated both in cells and by in vitro deubiquitination assays. These findings illustrate the dual regulatory roles of USP8 on both host antiviral factors and viral proteins, expanding our understanding of host-mediated HIV-1 restriction.
SN - 0022-538X
SN - 1098-5514
ER -