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| Status |
Public on May 29, 2024 |
| Title |
WSB1/2 target chromatin-bound lysine-methylated RelA for proteasomal degradation and NF-κB termination |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Proteasome-mediated degradation of chromatin-bound NF-κB is critical in terminating the transcription of pro-inflammatory genes and can be triggered by Set9-mediated lysine methylation of RelA subunit. However, the E3 ligase targeting methylated RelA remains unknown. Here, we identified two structurally similar WD-40 repeat (WDR) proteins, WSB1 and WSB2, as the E3s that recognize chromatin-bound methylated RelA for polyubiquitination and proteasomal degradation. WSB1/2 specifically recognized methylated lysines (K) 314 and 315 of RelA via their WDR domains. Deletion of WRD in WSB1/2 or mutation of K314/315 of RelA to arginines abolished the interaction between WSB1/2 and RelA. RNA-sequencing of TNF--stimulated WSB1/2 knockdown cells revealed that WSB1/2 negatively regulated a subset of NF-B target genes with reduced polyubiquitination of chromatin-bound RelA. TNF- stimulated the methylation of RelA and the subsequent recruitment of WSB1/2 to the promoters of these NF-B target genes to terminate the transcription. Computational modeling demonstrated that a highly conserved Asp within repeat 3 of WDR domains of WSB1/2 coordinated its interaction with K314/K315 of RelA, with a higher pKa when either of the lysines is methylated. Together, these findings identify novel E3 ligases that target chromatin-bound methylated RelA for proteolysis to prevent sustained NF-κB activation, providing new targets for therapeutic intervention of NF-κB-mediated inflammatory diseases.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for U2OS cells and its KD derivatives (shWSB2) under normal conditions and TNF-α stimulation (two replicates per sample)
Please note that each processed data file contains processed data for two samples and is linked to the corresponding '1' sample records.
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| Contributor(s) |
Zhang J, Du Y, Yu Y, He Y, Wu D, Jiang X, Sinclair M, Tajkhorshid E, Zheng Y, Hou Z, Chen L, Yang X |
| Citation(s) |
38452206 |
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| Submission date |
May 24, 2023 |
| Last update date |
May 30, 2024 |
| Contact name |
Yaning Du |
| E-mail(s) |
duyaning@sjtu.edu.cn
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| Phone |
13273359889
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| Organization name |
Shanghai Jiao Tong University
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| Street address |
shanghai
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| City |
shanghai |
| ZIP/Postal code |
200000 |
| Country |
China |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (8)
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| GSM7421595 |
U2OS cells, shWSB2, normal 2 |
| GSM7421596 |
U2OS cells, shControl, TNF-α 1 |
| GSM7421597 |
U2OS cells, shControl, TNF-α 2 |
| GSM7421598 |
U2OS cells, shWSB2, TNF-α 1 |
| GSM7421599 |
U2OS cells, shWSB2, TNF-α 2 |
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| Relations |
| BioProject |
PRJNA975809 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE233286_RAW.tar |
4.7 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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