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WSB1/2 target chromatin-bound lysine-methylated RelA for proteasomal degradation and NF-κB termination

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 the RelA subunit. However, the E3 ligase targeting methylated RelA remains unknown. Here, we find that two struc...

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Published in:Nucleic acids research 2024-05, Vol.52 (9), p.4969-4984
Main Authors: Zhang, Jie, Yu, Yuanyuan, Zou, Xiuqun, Du, Yaning, Liang, Qiankun, Gong, Mengyao, He, Yurong, Luo, Junqi, Wu, Dandan, Jiang, Xiaoli, Sinclair, Matt, Tajkhorshid, Emad, Chen, Hong-Zhuan, Hou, Zhaoyuan, Zheng, Yuejuan, Chen, Lin-Feng, Yang, Xiao-Dong
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Language:English
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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 the RelA subunit. However, the E3 ligase targeting methylated RelA remains unknown. Here, we find that two structurally similar substrate-recognizing components of Cullin-RING E3 ligases, WSB1 and WSB2, can recognize chromatin-bound methylated RelA for polyubiquitination and proteasomal degradation. We showed that WSB1/2 negatively regulated a subset of NF-κB target genes via associating with chromatin where they targeted methylated RelA for ubiquitination, facilitating the termination of NF-κB-dependent transcription. WSB1/2 specifically interacted with methylated lysines (K) 314 and 315 of RelA via their N-terminal WD-40 repeat (WDR) domains, thereby promoting ubiquitination of RelA. Computational modeling further revealed that a conserved aspartic acid (D) at position 158 within the WDR domain of WSB2 coordinates K314/K315 of RelA, with a higher affinity when either of the lysines is methylated. Mutation of D158 abolished WSB2's ability to bind to and promote ubiquitination of methylated RelA. Together, our study identifies a novel function and the underlying mechanism for WSB1/2 in degrading chromatin-bound methylated RelA and preventing sustained NF-κB activation, providing potential new targets for therapeutic intervention of NF-κB-mediated inflammatory diseases.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkae161