更新于：2024-11-01

FBXO3

更新于：2024-11-01

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). The SCF(FBXO3) complex specifically recognizes FBXL2 phosphorylated at 'Thr-404' and promotes its ubiquitination (By similarity).

关联

项与 FBXO3 相关的药物

KT-1002

靶点

FBXO3

作用机制

FBXO3抑制剂

在研机构

US Department of Veterans Affairs (District of Columbia) [+1]

原研机构

University of Pittsburgh Medical Center

在研适应症

溃疡性结肠炎 [+1]

非在研适应症

急性肺损伤 [+3]

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

Ginsenoside Rg1

靶点

FBXO3

作用机制

FBXO3抑制剂

在研机构

昆明医科大学

原研机构-

在研适应症

急性肺损伤

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

100 项与 FBXO3 相关的临床结果

登录后查看更多信息

100 项与 FBXO3 相关的转化医学

登录后查看更多信息

0 项与 FBXO3 相关的专利（医药）

登录后查看更多信息

286

项与 FBXO3 相关的文献（医药）

2024-10-01·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 ; Huang, Ziyan ; Rao, Guibo ; 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 ; Wang, Hsueh-Hsiao ; Yang, Po-Sheng ; 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.

2024-09-01·Journal of Magnetic Resonance Imaging

Assessment of Cerebral White Matter Involvement in Amyotrophic Lateral Sclerosis Patients With Disease Progression and Cognitive Impairment by Fixel‐Based Analysis and Neurite Orientation Dispersion and Density Imaging

Article

作者: Wang, Ximing ; Ma, Jiali ; Zhu, Mo ; Hu, Chunhong ; Zhu, Sijia ; Yu, Liqiang ; Wan, Jiayi ; Fang, Qi ; Xu, Rui ; Jiang, Bin ; Yu, Yixing

BackgroundPrevious studies using emerging diffusion MRI techniques have revealed damage to the white matter (WM) microstructure in amyotrophic lateral sclerosis (ALS), particularly the influence of crossed fibers, but there is a lack of subgroup analyses.PurposeTo detect WM microstructural changes in ALS patients using fixel‐based analysis (FBA) and neurite orientation dispersion and density imaging (NODDI) MRI.Study TypeProspective.PopulationThirty‐six ALS patients (aged 60.50 ± 9.5 years) and 25 healthy controls (HCs) (aged 58.90 ± 8.1 years).Field Strength/Sequence3 T; NODDI and FBA (b‐values = 0, 1000, and 2500 seconds/mm2).AssessmentSubgroups were performed according to progression rate and cognition, including fast and slow progression (FP/SP), ALS with and without cognitive impairment (ALS‐ci/ALS‐nci). Fiber density (FD), fiber‐bundle cross‐section (FC), combined fiber density and cross‐section (FDC), neurite density index (NDI), orientation dispersion index (ODI), isotropic volume fraction (ISO), and fractional anisotropy (FA) were calculated and their correlation with clinical variables examined.Statistical TestingChi‐square test, Mann–Whitney U test, two‐sample t test, partial correlation analysis, and false discovery rate (FDR) corrected. A P‐value <0.05 was considered significant.ResultsALS patients had lower FD and FDC values predominantly in the corticospinal tract (CST) and corpus callosum (CC) regions, as well as lower NDI value in the CC, radial crown, and internal capsule compared to HCs. Subgroup analysis based on progression rate and cognitive function showed significant differences in FBA results. The FC in the right CST region was significantly lower in the FP than SP, and the FD in the CC region was significantly lower in the ALS‐ci than ALS‐nci. Furthermore, a negative correlation was found between the mean FC value and the rate of progression in ALS patients (r = −0.408).Data ConclusionFBA is a powerful tool for detecting complex cerebral WM microstructural damage for evaluating ALS cognition and disease progression.

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