The epithelial C15ORF48/miR-147-NDUFA4 axis is an essential regulator of gut inflammation, energy metabolism, and the microbiome

• 成果类型: Article
• 署名作者: Xiong, Min; Liu, Ze; Wang, Bintao; Sokolich, Thomas; Graham, Natalie; Chen, Meirong; Wang, Wei-Le; Boldin, Mark P.
• 署名单位: City of Hope; Beckman Research Institute of City of Hope; University of Southern California; China Pharmaceutical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9309
• DOI: 10.1073/pnas.2315944121
• 发表日期: 2024-07-02
• 关键词: intestinal microbiota; ulcerative-colitis; gene; cells; expression; diagnosis; responses; microrna; immunity; disease

摘要

Chronic inflammation is epidemiologically linked to the pathogenesis of gastrointestinal diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, our understanding of the molecular mechanisms controlling gut inflammation remains insufficient, hindering the development of targeted therapies for IBD and CRC. In this study, we uncovered C15ORF48/miR - 147 as a negative regulator of gut inflammation, operating through the modulation of epithelial cell metabolism. C15ORF48/miR - 147 encodes two molecular products, C15ORF48 protein and miR - 147 - 3p microRNA, which are predominantly expressed in the intestinal epithelium. C15ORF48/miR - 147 ablation leads to gut dysbiosis and exacerbates chemically induced colitis in mice. C15ORF48 and miR - 147 - 3p work together to suppress colonocyte metabolism and inflammation by silencing NDUFA4 , a subunit of mitochondrial complex IV (CIV). Interestingly, the C15ORF48 protein, a structural paralog of NDUFA4, contains a unique C - terminal alpha- helical domain crucial for displacing NDUFA4 from CIV and its subsequent degradation. NDUFA4 silencing hinders NF -K B signaling activation and consequently attenuates inflammatory responses. Collectively, our findings have established the C15ORF48/miR - 147 - NDUFA4 molecular axis as an indispensable regulator of gut homeostasis, bridging mitochondrial metabolism and inflammation.