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 Patel, Benjamin S. Cho, Brian A. Yee, Lunfeng Zhang, Hiutung Chu, Sylvia Μ. Evans, G Yeo, Ye Zheng, Wendy Huang
Abstract
Retinoid-related orphan receptor (RAR) gamma (RORγt)–expressing regulatory T cells (RORγt + T regs ) 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 Il10 in RORγt + T regs . 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 Il10 in RORγt + T regs . T cell–specific Ddx5 knockout (DDX5 ΔT ) mice have augmented RORγt + T reg suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5 ΔT mice. The DDX5–HIF1α–IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.