SUMOylation of SARS-CoV-2 spike protein is a key target for broad-spectrum antiviral therapy.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-05-25 eCollection Date: 2025-01-01 DOI:10.7150/thno.111256
Xinyu Wang, Gaowei Hu, Yupeng Shao, Zhongwei Dong, Lina Liu, Yixuan Wang, Yaxi Xie, Nuoya Yu, Caixia Zhu, Fang Wei, Yuping Jia, Yuyan Wang, Qiliang Cai
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引用次数: 0

Abstract

Background: Dynamic SUMO modifications play crucial roles in orchestrating cellular response to various stimuli, including viral infection, and hold significant therapeutic potential. The Spike (S) protein, a surface glycoprotein of SARS-CoV-2 (a global health threat), serves as the key mediator for viral entry and is a critical target for drug development. However, the function of SUMOylation in the Spike protein remains largely unclear. Methods: The SUMO modification of Spike was assessed by immunoprecipitation (IP), denatured IP and immunoblotting assays in lung epithelial cells or SUMO deficient cell line models. The effect of Spike SUMOylation on viral infection was explored by site-direct mutation, cell-to-cell transmission, cell-free infection, quantitative PCR and immunofluorescence staining experiments. The role of Spike SUMOylation-derived peptides was investigated using viral intranasally infection, immunohistochemistry assay in transgenic mouse model. Results: SARS-CoV-2 infection triggers the relocation of SUMO1 to the cytoplasm and SUMO2 to the perinuclear region. Notably, SUMO1 knockout increases Spike trimer formation and its co-localization with SUMO2 at perinuclear puncta, which facilitates virion particle release. SUMO2 knockout leads to enhanced Spike cleavage and promotes viral cell-to-cell transmission. Further bioinformatic and immuno-precipitation analyses reveal that the Spike protein contains highly conserve SUMO-interacting motifs (SIMs) and selectively promotes either SUMO1 (via SIM1) or SUMO2 (via SIM3/4) modifications on lysine residues 129 and 1269, respectively. Importantly, these modifications can be efficiently disrupted by the SIM2 motif. A cell-penetrating peptide (cpSIM2), derived from the SIM2 motif, exhibits robust and broad-spectrum inhibitory activity against SARS-CoV-2 variants infection in vitro and in hACE2-transgenic mice model. Conclusions: This study uncovers critical features of SUMOylation in regulating Spike-mediated viral spread and pathogenesis, providing a potential broad-spectrum therapeutic target for drug development against emerging SARS-CoV-2 infection.

SARS-CoV-2刺突蛋白的sumo化是广谱抗病毒治疗的关键靶点。
背景:动态SUMO修饰在协调细胞对各种刺激(包括病毒感染)的反应中起着至关重要的作用,并具有显著的治疗潜力。Spike (S)蛋白是SARS-CoV-2(一种全球性健康威胁)的表面糖蛋白,是病毒进入的关键媒介,也是药物开发的关键靶点。然而,SUMOylation在Spike蛋白中的功能仍不清楚。方法:在肺上皮细胞或SUMO缺陷细胞系模型中,采用免疫沉淀(IP)、变性IP和免疫印迹法评价Spike对SUMO的修饰作用。通过位点直接突变、细胞间传播、无细胞感染、定量PCR和免疫荧光染色等实验,探讨了刺突SUMOylation对病毒感染的影响。采用病毒鼻内感染、免疫组织化学方法研究了Spike sumoylylation衍生肽在转基因小鼠模型中的作用。结果:SARS-CoV-2感染触发SUMO1向细胞质迁移,SUMO2向核周区迁移。值得注意的是,敲除SUMO1增加了Spike三聚体的形成及其与SUMO2在核周点位的共定位,促进了病毒粒子的释放。敲除SUMO2导致刺突断裂增强,并促进病毒细胞间传播。进一步的生物信息学和免疫沉淀分析表明,Spike蛋白含有高度保存的sumo相互作用基序(SIMs),并分别选择性地促进SUMO1(通过SIM1)或SUMO2(通过SIM3/4)在赖氨酸残基129和1269上的修饰。重要的是,这些修饰可以被SIM2基序有效地破坏。从SIM2基序衍生的细胞穿透肽(cpSIM2)在体外和hace2转基因小鼠模型中对SARS-CoV-2变异体感染表现出强大的广谱抑制活性。结论:本研究揭示了SUMOylation在调控spike介导的病毒传播和发病机制中的关键特征,为开发针对新发SARS-CoV-2感染的药物提供了潜在的广谱治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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