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

Genes

Xiaoyu Zhang¹  Gang Li¹  Yihan Zhao¹  Qiaoke Gong¹  Meijuan Zou¹  Ting Wu¹  Danli Jiang¹  Hang Su²  Di Wu³  Larry Moreland⁴ 

[1] Aging Institute at University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA;Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC 27514, USA;Department of Periodontology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;Division of Rheumatology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA;

关键词: CD40;    functional SNP;    autoimmune diseases;    ribosomal proteins;    NF-κB signaling;    transcriptional regulation network;   

DOI  :  10.3390/genes11121526

来源: DOAJ

【 摘 要 】

Previously, using FREP-MS, we identified a protein complex including eight proteins that specifically bind to the functional SNP (fSNP) rs6032664 at a CD40 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 bona fide CD40 transcriptional regulators via binding to rs6032664. In addition, we show that suppression of CD40 expression by RPL26 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 STAT4, CD86, TRAF1 and ICAM1 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: STAT4, CD86, TRAF1 and ICAM1, as well as the two proinflammatory cytokines: IL1β and IL6 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.

【 授权许可】

Unknown