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 α-helical domain crucial for displacing NDUFA4 from CIV and its subsequent degradation. NDUFA4 silencing hinders NF-κB 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.

中文翻译：

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上皮 C15ORF48/miR-147-NDUFA4 轴是肠道炎症、能量代谢和微生物组的重要调节因子


慢性炎症在流行病学上与胃肠道疾病的发病机制有关，包括炎症性肠病（IBD）和结直肠癌（CRC）。然而，我们对控制肠道炎症的分子机制的了解仍然不足，阻碍了 IBD 和 CRC 靶向治疗的开发。在这项研究中，我们发现C15ORF48/miR-147作为肠道炎症的负调节因子，通过调节上皮细胞代谢来发挥作用。 C15ORF48/miR-147编码两种分子产物，C15ORF48 蛋白和 miR-147-3p microRNA，它们主要在肠上皮中表达。 C15ORF48/miR-147消融会导致小鼠肠道菌群失调，并加剧化学诱导的结肠炎。 C15ORF48 和 miR-147-3p 共同作用，通过沉默抑制结肠细胞代谢和炎症NDUFA4 ，线粒体复合物 IV (CIV) 的一个亚基。有趣的是，C15ORF48 蛋白是 NDUFA4 的结构旁系同源物，含有一个独特的 C 端 α 螺旋结构域，对于从 CIV 中取代 NDUFA4 及其随后的降解至关重要。 NDUFA4沉默会阻碍 NF-κB 信号传导激活，从而减弱炎症反应。总的来说，我们的研究结果确定了C15ORF48/miR-147 - NDUFA4分子轴作为肠道稳态不可或缺的调节剂，在线粒体代谢和炎症之间架起桥梁。