A loss-of-function human ADAR variant activates innate immune response and promotes bowel inflammation

作者：Pengfei Xu, Yue Xi, Jong‐Won Kim, Min Zhang, Chen Gao, Yue Wang, Meishu Xu, Xingchen Wang, Songrong Ren, Da Yang, Qingde Wang, Wen Xie · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-63554-4 · 被引用次数：6 · 研究领域：RNA regulation and disease、Viral Infections and Immunology Research、RNA and protein synthesis mechanisms

Inflammatory bowel disease (IBD) arises from genetic-environmental interactions. Adenosine deaminases acting on RNA 1 (ADAR), an RNA-editing enzyme converting adenosine (A) to inosine (I), is essential for tissue homeostasis. Here we report that intestinal ADAR deficiency contributes to IBD pathogenesis in humans with reduced ADAR expression in patient intestinal crypts. Genetic or pharmacological inhibition of ADAR in mice causes spontaneous ileitis and colitis. Organoid studies show that ADAR loss leads to double-strand RNA (dsRNA) and endogenous retroviruses (ERVs) accumulation, disrupting intestinal homeostasis via melanoma differentiation-associated protein 5 (MDA5)-mediated dsRNA sensing and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. Editome analyses identify Mda5 as an ADAR target, and edited Mda5 exhibits impaired dsRNA sensing. The human ADAR p.N173S mutation is a loss-of-function variant that fails to rescue IBD in intestinal Adar deficient mice, whereas JAK1/2 inhibitor Ruxolitinib attenuates IBD. We conclude that the ADAR-dsRNA/ERVs-MDA5-JAK/STAT axis is a potential therapeutic target for IBD. Environmental and genetic factors affect the pathogenesis of inflammatory bowel disease (IBD). Here the authors show a loss of function Adenosine deaminases acting on RNA 1 (ADAR) variant that results in accumulation of dsRNA which is sensed by MDA5 and promotes bowel inflammation.