Zou, Meijuan and Zhang, Xiaoyu and Jiang, Danli and Zhao, Yihan and Wu, Ting and Gong, Qiaoke and Su, Hang and Wu, Di and Moreland, Larry and Li, Gang
(2020)
Transcriptional Regulation of CD40 Expression by 4 Ribosomal Proteins via a Functional SNP on a Disease-Associated CD40 Locus.
Genes, 11 (12).
p. 1526.
ISSN 2073-4425
Abstract
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.
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| Item Type: |
Article
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| Status: |
Published |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Zou, Meijuan | | | | | Zhang, Xiaoyu | | | | | Jiang, Danli | jiangd@pitt.edu | | | | Zhao, Yihan | | | | | Wu, Ting | tingwu@pitt.edu | | | | Gong, Qiaoke | | | | | Su, Hang | | | | | Wu, Di | | | | | Moreland, Larry | lwm5@pitt.edu | | | | Li, Gang | LIG@pitt.edu | | |
|
| Date: |
21 December 2020 |
| Date Type: |
Publication |
| Journal or Publication Title: |
Genes |
| Volume: |
11 |
| Number: |
12 |
| Publisher: |
MDPI AG |
| Page Range: |
p. 1526 |
| DOI or Unique Handle: |
10.3390/genes11121526 |
| Schools and Programs: |
School of Medicine > Medicine |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
CD40, functional SNP, autoimmune diseases, ribosomal proteins, NF-κB signaling, transcriptional regulation network |
| ISSN: |
2073-4425 |
| Official URL: |
http://dx.doi.org/10.3390/genes11121526 |
| Funders: |
Arthritis National Research Foundation, National Multiple Sclerosis Society, National Institutes of Health |
| Article Type: |
Research Article |
| Date Deposited: |
12 May 2022 20:10 |
| Last Modified: |
12 May 2022 20:10 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42978 |
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