Alternative mRNA polyadenylation regulates macrophage hyperactivation via the autophagy pathway

Macrophage hyperactivation is a hallmark of inflammatory diseases, yet the role of alternative polyadenylation (APA) of mRNAs in regulating innate immunity remains unclear. In this study, we focused on 3’UTR-APA and demonstrated that Nudt21, a crucial RNA-binding component of the 3’UTR-APA machinery...

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Veröffentlicht in:Cellular & molecular immunology 2024-12, Vol.21 (12), p.1522-1534
Hauptverfasser: Chen, Yunzhu, Chen, Baiwen, Li, Jingyu, Li, Haixin, Wang, Gaoyang, Cai, Xuemin, Zhang, Qianqian, Liu, Xiaoxu, Kan, Chen, Wang, Lei, Wang, Zhengting, Li, Hua-Bing
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Sprache:eng
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Zusammenfassung:Macrophage hyperactivation is a hallmark of inflammatory diseases, yet the role of alternative polyadenylation (APA) of mRNAs in regulating innate immunity remains unclear. In this study, we focused on 3’UTR-APA and demonstrated that Nudt21, a crucial RNA-binding component of the 3’UTR-APA machinery, is significantly upregulated in various inflammatory conditions. By utilizing myeloid-specific Nudt21-deficient mice, we revealed a protective effect of Nudt21 depletion against colitis and severe hyperinflammation, primarily through diminished production of proinflammatory cytokines. Notably, Nudt21 regulates the mRNA stability of key autophagy-related genes, Map1lc3b and Ulk2 , by mediating selective 3’UTR polyadenylation in activated macrophages. As a result, Nudt21-deficient macrophages display increased autophagic activity, which leads to reduced cytokine secretion. Our findings highlight an unexplored role of Nudt21-mediated 3’UTR-APA in modulating macrophage autophagy and offer new insights into the modulation of inflammation and disease progression.
ISSN:2042-0226
1672-7681
2042-0226
DOI:10.1038/s41423-024-01237-8