ZNF598 enhances FAT10-mediated non-covalent stabilization of Tat to promote HIV-1 transcription and replication

Hongyun Shi; Panpan Quan; Chaohui Tang; Yubao Hou; Huihan Wang; Yingchao Wang; Hong Wang; Wenyan Zhang

doi:10.1016/j.virs.2026.07.007

October 2026

Citation: Hongyun Shi, Panpan Quan, Chaohui Tang, Yubao Hou, Huihan Wang, Yingchao Wang, Hong Wang, Wenyan Zhang. ZNF598 enhances FAT10-mediated non-covalent stabilization of Tat to promote HIV-1 transcription and replication .VIROLOGICA SINICA, 2026, 41(5) : 1066-1077. http://dx.doi.org/10.1016/j.virs.2026.07.007

ZNF598 enhances FAT10-mediated non-covalent stabilization of Tat to promote HIV-1 transcription and replication

Hongyun Shi ^a,b ,
Panpan Quan ^c ,
Chaohui Tang ^d ,
Yubao Hou ^a ,
Huihan Wang ^a ,
Yingchao Wang ^b ,
Hong Wang ^{a
,,} ,
Wenyan Zhang ^{a
,,}

a. Institute of Virology and AIDS Research, Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130021, China;
b. Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China;
c. Department of Cadre’s Wards Ultrasound Diagnostics, Ultrasound Diagnostic Center, The First Hospital of Jilin University, Changchun, 130021, China;
d. Hyperbaric Oxygen Department, The First Hospital of Jilin University, Changchun, 130021, China

Corresponding author: Hong Wang, wanghong_2020@jlu.edu.cn
Wenyan Zhang, zhangwenyan@jlu.edu.cn
Received Date: 08 April 2026
Accepted Date: 17 July 2026
Available online: 20 July 2026

Abstract

Human immunodeficiency virus type 1 (HIV-1) Tat is essential for efficient viral transcription and replication, and its stability is tightly controlled by host factors. In our previous study, we showed that ZNF598 stabilizes Tat and promotes HIV-1 replication through an E3 ligase activity-independent mechanism. Here, we identify FAT10 as a critical mediator of this effect. FAT10 knockout in HEK293T cells or FAT10 knockdown in Jurkat T-cell infection models markedly impaired the ability of ZNF598 to suppress Tat K48-linked ubiquitination, increase Tat abundance, and enhance HIV-1 replication. Mechanistically, FAT10 reduced Tat K48-linked ubiquitination, stabilized Tat, and promoted HIV-1 transcription and replication. Direct GST pull-down assays further demonstrated that FAT10 directly binds Tat in vitro, and this interaction was retained by a FAT10 mutant lacking the C-terminal diglycine motif, supporting a predominantly non-covalent mechanism rather than canonical FAT10ylation. Consistently, ZNF598 enhanced the FAT10-Tat interaction, whereas ZNF598 knockdown attenuated FAT10-mediated Tat stabilization and proviral effects. In addition, the N-terminal 1-32 amino acids of Tat were required for responsiveness to both ZNF598 and FAT10. Finally, FAT10 expression was increased in HIV-1-infected cells and in CD4⁺ T cells from HIV-infected individuals, where it was associated with clinical markers of disease activity and viral load. Together, these findings define a ZNF598-FAT10-Tat regulatory axis that promotes HIV-1 transcription and replication.
- HIV-1
- , Tat
- , ZNF598
- , FAT10
- , Ubiquitination

Electronic Supplementary Material

10.1016j.virs.2026.07.007-ESM.docx
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