RNA binding protein DDX5 restricts RORγt+ Treg 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

doi:10.1126/sciadv.add6165

RNA binding protein DDX5 restricts RORγt⁺ T_reg suppressor function to promote intestine inflammation

Sci Adv. 2023 Feb 3;9(5):eadd6165. doi: 10.1126/sciadv.add6165. Epub 2023 Feb 1.

Authors

Shengyun Ma¹, Qiyuan Yang², Nicholas Chen¹, Anna Zheng¹, Nazia Abbasi¹, Gaowei Wang³, Parth R Patel¹, Benjamin S Cho¹, Brian A Yee¹, Lunfeng Zhang⁴, Hiutung Chu^{5

6}, Sylvia M Evans^{4

7

8}, Gene W Yeo¹, Ye Zheng², Wendy Jia Men Huang¹

Affiliations

¹ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
² NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.
³ Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁴ Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA.
⁵ Department of Pathology, University of California San Diego, La Jolla, CA, USA.
⁶ Chiba University-UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (cMAV), University of California San Diego, La Jolla, CA, USA.
⁷ Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
⁸ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.

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.

MeSH terms

Animals
DEAD-box RNA Helicases / genetics
DEAD-box RNA Helicases / metabolism
Gene Expression Regulation
Humans
Interleukin-10* / genetics
Mice
Nuclear Receptor Subfamily 1, Group F, Member 3* / genetics
Nuclear Receptor Subfamily 1, Group F, Member 3* / metabolism
Protein Binding
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Transcription Factors / metabolism

Substances

Interleukin-10
Nuclear Receptor Subfamily 1, Group F, Member 3
Transcription Factors
RNA-Binding Proteins
DEAD-box RNA Helicases
Ddx5 protein, human

Abstract

MeSH terms

Substances

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