RNA binding protein DDX5 restricts RORγt<sup>+</sup> T<sub>reg</sub> suppressor function to promote intestine inflammation.
Shengyun Ma, Qiyuan Yang, Nicholas Chen, Anna Zheng, Nazia Abbasi, Gaowei Wang, Parth R Patel, Benjamin S Cho, Brian A Yee, Lunfeng Zhang, Hiutung Chu, Sylvia M Evans, Gene W Yeo, Ye Zheng, Wendy Jia Men Huang
Science advances · 2023 · Vol. 9 (5) · pp. eadd6165
Abstract
Retinoid-related orphan receptor (RAR) gamma (RORγt)-expressing regulatory T cells (RORγt<sup>+</sup> T<sub>regs</sub>) play pivotal roles in preventing T cell hyperactivation and maintaining tissue homeostasis, in part by secreting the anti-inflammation cytokine interleukin-10 (IL-10). Here, we report that hypoxia-induced factor 1α (HIF1α) is the master transcription factor for <i>Il10</i> in RORγt<sup>+</sup> T<sub>regs</sub>. This critical anti-inflammatory pathway is negatively regulated by an RNA binding protein DEAD box helicase 5 (DDX5). As a transcriptional corepressor, DDX5 restricts the expression of HIF1α and its downstream target gene <i>Il10</i> in RORγt<sup>+</sup> T<sub>regs</sub>. T cell-specific <i>Ddx5</i> knockout (DDX5<sup>ΔT</sup>) mice have augmented RORγt<sup>+</sup> T<sub>reg</sub> suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5<sup>ΔT</sup> mice. The DDX5-HIF1α-IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.
Linked datasets 1
DDX5 RNA interactome in cultured T cells
Mus musculus
8 data files
| File | Type | Size |
|---|---|---|
| COLLAB16_DDX5-R1-input_S115_L008_R1_001.fastq.gz | RIP-Seq | 901.7 MB |
| COLLAB17_DDX5-R2-input_S116_L008_R1_001.fastq.gz | RIP-Seq | 790.7 MB |
| COLLAB18_DDX5-R1-IP_S117_L008_R1_001.fastq.gz | RIP-Seq | 1.2 GB |
| COLLAB19_DDX5-R2-IP_S118_L008_R1_001.fastq.gz | RIP-Seq | 912.7 MB |
| SRR12563740_GSM4760290 | RIP-Seq | 1.2 GB |
| SRR12563741_GSM4760291 | RIP-Seq | 901.0 MB |
| SRR12563742_GSM4760292 | RIP-Seq | 912.0 MB |
| SRR12563743_GSM4760293 | RIP-Seq | 790.0 MB |
Potentially related datasets 3
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
| Accession | Source | Title |
|---|---|---|
| GSE134809 | GSE · GEO GEO ↗ | Single-cell analysis of Crohnâs disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy |
| GSE162335 | GSE · GEO GEO ↗ | Transcriptional Survey of Ileal-Anal Pouch Immune Cells from Ulcerative Colitis |
| GSE157259 | GSE · GEO GEO ↗ | DDX5 RNA interactome in cultured T cells |
Analysis pipelines 3
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE134809 Data Processing geo_data_processing | — | 5 | GSE134809 |
| GSE157259 eCLIP Data Processing geo_data_processing | eCLIP | 22 | GSE157259 |
| GSE162335 scRNA-seq Data Processing geo_data_processing | scRNA-seq | 2 | GSE162335 |
Funding 11 grants
| Grant | Funder |
|---|---|
| S10 OD026929 | NIH HHS (United States) |
| R01 HG004659 | NHGRI NIH HHS (United States) |
| P30 CA023100 | NCI NIH HHS (United States) |
| U41 HG009889 | NHGRI NIH HHS (United States) |
| P30 CA014195 | NCI NIH HHS (United States) |
| R01 AI151123 | NIAID NIH HHS (United States) |
| R21 AI178938 | NIAID NIH HHS (United States) |
| R00 DK110534 | NIDDK NIH HHS (United States) |
| R01 AI107027 | NIAID NIH HHS (United States) |
| R21 AI154919 | NIAID NIH HHS (United States) |
| R01 GM124494 | NIGMS NIH HHS (United States) |