Dataset Information

A systems-wide screen identifies substrates of the SCF-beta-TrCP ubiquitin ligase.

ABSTRACT: Data from ProteomeXchange, PXD ID: PXD001224. File: OR3_100623_BTrCP_EV_IP_Band01.mzml. Published as part of Sci Signal. 2014 Dec 16;7(356):rs8 . From the Abstract: {{i}} ... We developed a combined bioinformatics and affinity purification-mass spectrometry (AP-MS) workflow for the system-wide identification of substrates of SCF(beta-TrCP), a member of the SCF family of ubiquitin ligases. These ubiquitin ligases are characterized by a multisubunit architecture typically consisting of the invariable subunits Rbx1, Cul1, and Skp1 and one of 69 F-box proteins ... {{/i}}

INSTRUMENT(S): Instrument

ORGANISM(S): Homo_sapiens_viruses, Human_female

DISEASE(S): Not Available

SUBMITTER: Low TY, et al.

PROVIDER: GPM32320006530 | GPMDB |

REPOSITORIES: GPMDB

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A systems-wide screen identifies substrates of the SCFβTrCP ubiquitin ligase.

Low Teck Yew TY Peng Mao M Magliozzi Roberto R Mohammed Shabaz S Guardavaccaro Daniele D Heck Albert J R AJ

Science signaling 20141216 356

Cellular proteins are degraded by the ubiquitin-proteasome system (UPS) in a precise and timely fashion. Such precision is conferred by the high substrate specificity of ubiquitin ligases. Identification of substrates of ubiquitin ligases is crucial not only to unravel the molecular mechanisms by which the UPS controls protein degradation but also for drug discovery purposes because many established UPS substrates are implicated in disease. We developed a combined bioinformatics and affinity pur ...[more]

PMID: 25515538

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Project description:Background: After spinal cord injury (SCI), lipid metabolism dysregulation at the lesion site exacerbates secondary damage. The transcription factor pu.1 has been implicated as a negative regulator of multiple lipid metabolism-related genes and pathways. However, its role in post-SCI lipid metabolism remains unclear. Methods: We employed a mouse model of complete T10 crush SCI. Non-targeted metabolomics and bioinformatics analysis were utilized to investigate lipid metabolism at the lesion site after SCI. Polarized light imaging was used to evaluate the presence of cholesterol crystals. DB1976, a specific inhibitor of pu.1, was administered to examine its impact on local lipid metabolism after SCI. Immunofluorescence staining was performed to assess pu.1 expression and distribution, and to evaluate lipid droplet formation, astrocytic/fibrotic scar development, inflammatory cell infiltration and tight junctions within the vasculature. Results: Non-targeted metabolomics and bioinformatics analyses revealed significant alterations in lipid metabolism components after SCI. Moreover, immunofluorescence staining and polarized light imaging demonstrated substantial BODIPY+ lipid droplet accumulation and persistent cholesterol crystal formation at the lesion site after SCI. Increased pu.1 expression was predominantly observed within macrophages/microglia at the lesion site after SCI. DB1976 treatment significantly mitigated lipid droplet accumulation and cholesterol crystal formation, reduced CD68+ macrophage/microglial infiltration and attenuated fibrotic scar formation. Moreover, DB1976 treatment promoted the expression of claudin-5 and zonula occludens-1 between vascular endothelial cells and enhanced GFAP+ glial connectivity after SCI. Conclusions: Our study reveals a significant correlation between lipid metabolism disturbance post-SCI and transcription factor pu.1 upregulation, specifically in macrophages/microglia at the lesion site. Thus, targeted pu.1 modulation has the potential to yield promising results by substantially diminishing the deposition of lipid metabolism byproducts at the lesion site and fostering a milieu conducive to SCI repair.

Dataset Information

A systems-wide screen identifies substrates of the SCF-beta-TrCP ubiquitin ligase.

Publications

A systems-wide screen identifies substrates of the SCFβTrCP ubiquitin ligase.

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