Transcriptional Regulation of CD40 Expression by 4 Ribosomal Proteins via a Functional SNP on a Disease-Associated CD40 Locus

• Published in: Genes 2020-12, Vol.11 (12), p.1526
• Main Authors: Zou, Meijuan, Zhang, Xiaoyu, Jiang, Danli, Zhao, Yihan, Wu, Ting, Gong, Qiaoke, Su, Hang, Wu, Di, Moreland, Larry, Li, Gang
• Format: Article
• Language: English
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes11121526

Previously, using FREP-MS, we identified a protein complex including eight proteins that specifically bind to the functional SNP (fSNP) rs6032664 at a locus associated with autoimmune diseases. Among these eight proteins, four are ribosomal proteins RPL26, RPL4, RPL8, and RPS9 that normally make up the ribosomal subunits involved in the cellular process of protein translation. So far, no publication has shown these ribosomal proteins function as transcriptional regulators. In this work, we demonstrate that four ribosomal proteins: RPL26, RPL4, RPL8, and RPS9 are transcriptional regulators via binding to rs6032664. In addition, we show that suppression of expression by RNAi knockdown inactivates NF-κB p65 by dephosphorylation via NF-κB signaling pathway in fibroblast-like synoviocytes (FLS), which further reduces the transcription of disease-associated risk genes such as and as the direct targets of NF-κB p65. Based on these findings, a disease-associated risk gene transcriptional regulation network (TRN) is generated, in which decreased expression of, at least, RPL26 results in the downregulation of risk genes: and as well as the two proinflammatory cytokines: and via CD40-induced NF-κB signaling. We believe that further characterization of this disease-associated TRN in the CD40-induced NF-κB signaling by identifying both the upstream and downstream regulators will potentially enable us to identify the best targets for drug development.