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更新于：2025-05-07

FBXO3

更新于：2025-05-07

基本信息

别名

F-box only protein 3、F-box protein 3、FBA

+ [2]

简介

Substrate recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex, SCF(FBXO3), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:18809579, PubMed:26037928). Mediates the ubiquitination of HIPK2 and probably that of EP300, leading to rapid degradation by the proteasome (PubMed:18809579). In the presence of PML, HIPK2 ubiquitination still occurs, but degradation is prevented (PubMed:18809579). PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53-dependent transactivation (PubMed:18809579). The SCF(FBXO3) also acts as a regulator of inflammation by mediating ubiquitination and degradation of FBXL2 in response to lipopolysaccharide (LPS) (PubMed:26037928, PubMed:27010866). The SCF(FBXO3) complex specifically recognizes FBXL2 phosphorylated at 'Thr-404' and promotes its ubiquitination (PubMed:27010866). (Microbial infection) Associates with the Rift valley fever virus NSs to form a remodeled E3 ligase that triggers efficient proteasomal degradation of targeted proteins. The filamentous E3 ligase targets the TFIIH complex leading to robust inhibition of antiviral immunity and enhances viral pathogenesis.

关联

项与 FBXO3 相关的药物

Ginsenoside Rg1

靶点

APP x FBXO3

作用机制

APP抑制剂 [+1]

在研机构

昆明医科大学 [+2]

原研机构-

在研适应症

术后认知功能障碍 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

KT-1002

靶点

FBXO3

作用机制

FBXO3抑制剂

在研机构-

原研机构

Va Pittsburgh Healthcare System [+1]

在研适应症-

非在研适应症

溃疡性结肠炎 [+2]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 FBXO3 相关的临床试验

ChiCTR2200055194

/ Recruiting早期临床1期IIT

A randomized controlled clinical trial of ginsenoside Rg1 combined with reduced glutathione in the treatment of diabetic wounds

开始日期2022-01-03

申办/合作机构-

100 项与 FBXO3 相关的临床结果

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100 项与 FBXO3 相关的转化医学

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0 项与 FBXO3 相关的专利（医药）

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项与 FBXO3 相关的文献（医药）

2024-11-01·Journal of Proteome Research

Distinct Regions within SAP25 Recruit O-Linked Glycosylation, DNA Demethylation, and Ubiquitin Ligase and Hydrolase Activities to the Sin3/HDAC Complex

Article

作者: Thornton, Janet ; Sardiu, Mihaela E. ; Goswami, Pratik ; Washburn, Michael P. ; Florens, Laurence ; Banks, Charles A.S. ; Bengs, Bethany D.

Sin3 is an evolutionarily conserved repressor protein complex mainly associated with histone deacetylase (HDAC) activity. Many proteins are part of Sin3/HDAC complexes, and the function of most of these members remains poorly understood. SAP25, a previously identified Sin3A associated protein of 25 kDa, has been proposed to participate in regulating gene expression programs involved in the immune response but the exact mechanism of this regulation is unclear. SAP25 is not expressed in HEK293 cells, which hence serve as a natural knockout system to decipher the molecular functions uniquely carried out by this Sin3/HDAC subunit. Using molecular, proteomic, protein engineering, and interaction network approaches, we show that SAP25 interacts with distinct enzymatic and regulatory protein complexes in addition to Sin3/HDAC. Additional proteins uniquely recovered from the Halo-SAP25 pull-downs included the SCF E3 ubiquitin ligase complex SKP1/FBXO3/CUL1 and the ubiquitin carboxyl-terminal hydrolase 11 (USP11). Furthermore, mutational analysis demonstrates that distinct regions of SAP25 participate in its interaction with USP11, OGT/TETs, and SCF(FBXO3). These results suggest that SAP25 may function as an adaptor protein to coordinate the assembly of different enzymatic complexes to control Sin3/HDAC-mediated gene expression. The data were deposited with the MASSIVE repository with the identifiers MSV000093576 and MSV000093553.

2024-11-01·Cell

Rift Valley fever virus coordinates the assembly of a programmable E3 ligase to promote viral replication

Article

作者: Guan, Zhenqiong ; Cao, Sheng ; Zhang, Yulan ; Lozach, Pierre-Yves ; Li, Huiling ; Li, Shufen ; Rao, Guibo ; Huang, Ziyan ; Zhang, Chongtao ; Peng, Ke

Viruses encode strategies to degrade cellular proteins to promote infection and pathogenesis. Here, we revealed that the non-structural protein NSs of Rift Valley fever virus forms a filamentous E3 ligase to trigger efficient degradation of targeted proteins. Reconstitution in vitro and cryoelectron microscopy analysis with the 2.9-Å resolution revealed that NSs forms right-handed helical fibrils. The NSs filamentous oligomers associate with the cellular FBXO3 to form a remodeled E3 ligase. The NSs-FBXO3 E3 ligase targets the cellular TFIIH complex through the NSs-P62 interaction, leading to ubiquitination and proteasome-dependent degradation of the TFIIH complex. NSs-FBXO3-triggered TFIIH complex degradation resulted in robust inhibition of antiviral immunity and promoted viral pathogenesis in vivo. Furthermore, it is demonstrated that NSs can be programmed to target additional proteins for proteasome-dependent degradation, serving as a versatile targeted protein degrader. These results showed that a virulence factor forms a filamentous and programmable degradation machinery to induce organized degradation of cellular proteins to promote viral infection.

2024-09-25·The Journal of Neuroscience

The Transcription Factor Tbx5-Dependent Epigenetic Modification Contributes to Neuropathic Allodynia by Activating TRPV1 Expression in the Dorsal Horn

Article

作者: Lin, Tzer-Bin ; Hsieh, Ming-Chun ; Peng, Hsien-Yu ; Lai, Cheng-Yuan ; Yang, Po-Sheng ; Wang, Hsueh-Hsiao ; Lin, Kuan-Hung ; Chou, Dylan

Nerve injury can induce aberrant changes in the spine; these changes are due to, or at least partly governed by, transcription factors that contribute to the genesis of neuropathic allodynia. Here, we showed that spinal nerve ligation (SNL, a clinical neuropathic allodynia model) increased the expression of the transcription factor Tbx5 in the injured dorsal horn in male Sprague Dawley rats. In contrast, blocking this upregulation alleviated SNL-induced mechanical allodynia, and there was no apparent effect on locomotor function. Moreover, SNL-induced Tbx5 upregulation promoted the recruitment and interaction of GATA4 and Brd4 by enhancing its binding activity to H3K9Ac, which was enriched at theTrpv1promotor, leading to an increase in TRPV1 transcription and the development of neuropathic allodynia. In addition, nerve injury-induced expression of Fbxo3, which abates Fbxl2-dependent Tbx5 ubiquitination, promoted the subsequent Tbx5-dependent epigenetic modification of TRPV1 expression during SNL-induced neuropathic allodynia. Collectively, our findings indicated that spinal Tbx5-dependent TRPV1 transcription signaling contributes to the development of neuropathic allodynia via Fbxo3-dependent Fbxl2 ubiquitination and degradation. Thus, we propose a potential medical treatment strategy for neuropathic allodynia by targeting Tbx5.

项与 FBXO3 相关的新闻（医药）

2024-10-04

·生物探索

Cell | 裂谷热病毒突破免疫防线：NSs-FBXO3复合体如何介导细胞蛋白降解

引言裂谷热病毒（Rift Valley fever virus, RVFV），是一种蚊媒传播的致病性人畜共患病毒，其对于牛、羊等多种家畜可造成致死性的感染，而病毒感染人体后可引起脑炎、出血热等临床症状，重症感染者具有较高的病死率。由于缺乏有效的抗病毒药物及人用疫苗，并具有大流行的潜在风险，裂谷热病毒被世界卫生组织持续列为亟待开展研究的病原体。然而，裂谷热病毒感染致病的关键机制目前尚不清楚，阻碍了针对裂谷热病毒抗病毒药物的研发。 2024年10月3日，中国科学院武汉病毒研究所彭珂研究员和曹晟研究员团队在Cell上发表了题为 Rift Valley fever virus coordinates the assembly of a programmable E3-ligase to promote viral replication的研究论文。该研究揭示了裂谷热病毒非结构蛋白NSs重塑宿主E3泛素连接酶系统性抑制宿主抗病毒免疫的致病新机制，也为裂谷热病毒抗病毒药物研发提供了新思路。为探究裂谷热病毒感染致病的机理，研究团队针对裂谷热病毒的关键毒力因子非结构蛋白NSs开展研究，发现NSs蛋白通过组装形成纤维状结构挟持了宿主E3泛素连接酶组分FBXO3，重塑形成了一种纤维状的FBXO3-NSs泛素连接酶。同时，NSs通过对接宿主转录因子复合物IIH（Transcription factor IIH, TFIIH）的亚基，由纤维状FBXO3-NSs泛素连接酶引发了TFIIH复合体多亚基的泛素化修饰及蛋白酶体途径降解，引发了宿主细胞的转录抑制。进一步研究发现，NSs诱发的TFIIH复合物降解系统性抑制了抗病毒IFN-I干扰素通路相关基因的表达，显著促进了病毒复制。动物模型感染实验证明，病毒重塑形成的纤维状FBXO3-NSs泛素连接酶所介导的宿主蛋白靶向降解对于病毒感染引起的多脏器损伤及致病性极为重要，而破坏纤维状FBXO3-NSs泛素连接酶的形成可使得裂谷热病毒感染致死率降低90%以上。模式图（Credit: Cell）上述研究揭示了病毒非结构蛋白以一种“以子之矛、攻子之盾”的方式，挟持宿主E3泛素连接酶，通过重塑E3泛素连接酶的修饰谱降解调控宿主抗病毒免疫的关键蛋白，从而系统性抑制宿主抗病毒免疫的感染致病新机制，也为以病毒非结构蛋白做为抗病毒药物研发的新靶点提供了理论依据。参考文献 https://doi.org/10.1016/j.cell.2024.09.008 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

疫苗蛋白降解靶向嵌合体免疫疗法