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WSB1/2 target chromatin-bound lysine-methylated RelA for proteasomal degradation and NF-κB termination.
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.
Afiliación
  • Zhang J; Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
  • Yu Y; The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Zou X; Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Du Y; Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
  • Liang Q; Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
  • Gong M; The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • He Y; Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Luo J; The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Wu D; Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Jiang X; The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Sinclair M; Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Tajkhorshid E; The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Chen HZ; Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Hou Z; Shanghai Institute of Immunology, and Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • Zheng Y; Shanghai Institute of Immunology, and Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • Chen LF; Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, and Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Yang XD; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Nucleic Acids Res ; 52(9): 4969-4984, 2024 May 22.
Article en En | MEDLINE | ID: mdl-38452206
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cromatina / Complejo de la Endopetidasa Proteasomal / Factor de Transcripción ReIA / Ubiquitinación Límite: Humans Idioma: En Revista: Nucleic Acids Res Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cromatina / Complejo de la Endopetidasa Proteasomal / Factor de Transcripción ReIA / Ubiquitinación Límite: Humans Idioma: En Revista: Nucleic Acids Res Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido