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

. doi: 10.1016/j.virs.2026.07.007

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通过增强FAT10介导的Tat非共价稳定促进HIV-1转录与复制

师鸿运 ^a,b ,
权盼盼 ^c ,
唐朝辉 ^d ,
侯玉宝 ^a ,
王荟涵 ^a ,
王英超 ^b ,
王虹 ^a,, ,
和张文艳 ^a,,

a. 吉林大学第一医院感染性疾病与病原生物学中心, 艾滋病与病毒研究所, 教育部器官再生与移植重点实验室, 吉林省长春市, 中国, 130021;
b. 吉林大学第一医院普通外科中心肝胆胰外科, 吉林省长春市, 中国, 130021;
c. 吉林大学第一医院超声诊断中心干部病房超声科, 吉林省长春市, 中国, 130021;
d. 吉林大学第一医院高压氧科, 吉林省长春市, 中国, 130021

通讯作者： 王虹, wanghong_2020@jlu.edu.cn; 和张文艳, zhangwenyan@jlu.edu.cn
收稿日期： 2026-04-08
录用日期： 2026-07-17

摘要

人类免疫缺陷病毒1型（HIV-1）的Tat蛋白对高效的病毒转录和复制至关重要，其稳定性由宿主因子严格调控。在我们先前的研究中，已证明ZNF598通过一种不依赖E3连接酶活性的机制稳定Tat并促进HIV-1的复制。本研究进一步发现FAT10是实现这一效应的关键介导蛋白。在HEK293T细胞中敲除FAT10，或在Jurkat T细胞感染模型中敲低FAT10，均显著削弱了ZNF598抑制Tat K48连接泛素化、增加Tat丰度以及增强HIV-1复制的能力。从机制上分析，FAT10可减少Tat K48连接的泛素化，稳定Tat，并促进HIV-1的转录与复制。直接的GST亲和力检测进一步证实，FAT10在体外能直接结合Tat，且该相互作用在缺乏C端二甘氨酸结构域的FAT10突变体中仍得以保留，表明其主要通过非共价机制发挥作用，而非经典的FAT10泛素化。此外，ZNF598增强了FAT10与Tat之间的相互作用，而ZNF598的敲低则减弱了FAT10介导的Tat稳定化及病毒复制促进效应。此外，Tat的N端1-32个氨基酸对ZNF598和FAT10均具有响应性。最后，在HIV-1感染的细胞以及HIV感染者CD4+ T细胞中，FAT10的表达水平升高，并与疾病活动性和病毒载量的临床指标相关。综上所述，这些发现定义了一个由ZNF598-FAT10-Tat组成的调控轴，该轴促进HIV-1的转录和复制。
- HIV-1
- , Tat
- , ZNF598
- , FAT10
- , 泛素

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

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

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

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