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

Autor:	Xiong M; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010., Liu Z; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033., Wang B; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010., Sokolich T; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010., Graham N; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010., Chen M; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China., Wang WL; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010., Boldin MP; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jul 02; Vol. 121 (27), pp. e2315944121. Date of Electronic Publication: 2024 Jun 25.
DOI:	10.1073/pnas.2315944121
Abstrakt:	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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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