Last update 01 Nov 2024

FBXO3

Last update 01 Nov 2024

Basic Info

Synonyms

F-box only protein 3, F-box protein 3, FBA

+ [2]

Introduction

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).

Drugs associated with FBXO3

KT-1002

Target

FBXO3

Mechanism

FBXO3 inhibitors

Active Org.

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

Originator Org.

University of Pittsburgh Medical Center

Active Indication

Colitis, Ulcerative [+1]

Inactive Indication

Acute Lung Injury [+3]

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Ginsenoside Rg1

Target

FBXO3

Mechanism

FBXO3 inhibitors

Active Org.

Kunming Medical University

Originator Org.-

Active Indication

Acute Lung Injury

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with FBXO3

100 Translational Medicine associated with FBXO3

0 Patents (Medical) associated with FBXO3

286

Literatures (Medical) associated with FBXO3

01 Oct 2024·Cell

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

Article

Author: 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.

25 Sep 2024·The Journal of Neuroscience

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

Article

Author: 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.

01 Sep 2024·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

Author: 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.

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FBXO3

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