Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid–binding protein 1 (FABP1). However, little is known of the upstream mechanisms driving their expressions in different segments of the intestinal tract. Here, we report that the RNA-binding protein DDX5 binds to the mRNA transcripts of C3 and Fabp1 to augment their expressions posttranscriptionally. Knocking out DDX5 in epithelial cells protected mice from intestinal tumorigenesis and dextran sodium sulfate (DSS)–induced colitis. Identification of DDX5 as a common upstream regulator of tissue-specific oncogenic molecules provides an excellent therapeutic target for intestinal diseases.

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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.

Adenosine deaminases acting on RNA (ADARs) catalyze the most common RNA modification in mammals, but it remains to be elucidated how their RNA editing dependent and independent activities contribute to host immunity. Here, we report dynamic changes in ADARs expressions and global adenosine-to-inosin (A-to-I) editome during T helper cell differentiation. In differentiated T helper 17 (Th17) cells, transcription of the ADAR2 encoding locus is potentiated by an intragenic super enhancer and splicing of the ADAR2 encoding transcript is further facilitated by a DEAD-box RNA helicase, DDX5. In an editing-independent manner, ADAR2 negatively regulates Hypoxia-Inducible Factor 1-alpha (HIF1alpha) expression to limit the production of interleukin-10 (IL-10) in Th17 cells. These results demonstrate ADAR2 and the upstream mechanisms governing its expression as critical regulators of Th17 cell effector function.

Unresolved inflammation causes tissue damage and contributes to autoimmune conditions. However, the molecules and mechanisms controlling T cell mediated inflammation remain to be fully elucidated. Here, we report an unexpected role of the RAR-Related Orphan Receptor-gamma protein (RORγt) in resolving tissue inflammation. Single-cell RNA-seq (scRNA-seq) revealed that an evolutionarily conserved serine 182 residue on ROR&γt (RORγtS182) is critical for restricting IL-1β-mediated Th17 activities and promoting anti-inflammatory cytokine IL-10 production in RORγt+ Treg cells in inflamed tissues. Phospho-null RORγtS182A knock-in mice experienced delayed recovery and succumbed to exacerbated diseases after dextran sulfate sodium (DSS) induced colitis and experimental autoimmune encephalomyelitis (EAE) challenge. Together, these results highlight the essential role of ROR&γtS182 in resolving T cell mediated tissue inflammation, providing a potential therapeutic target to combat autoimmune diseases.