Alternative mRNA polyadenylation regulates macrophage hyperactivation via the autophagy pathway

Yunzhu Chen; Baiwen Chen; Jingyu Li; Haixin Li; Gaoyang Wang; Xuemin Cai; Qianqian Zhang; Xiaoxu Liu; Chen Kan; Lei Wang; Zhengting Wang; Hua-Bing Li

doi:10.1038/s41423-024-01237-8

Alternative mRNA polyadenylation regulates macrophage hyperactivation via the autophagy pathway

Cell Mol Immunol. 2024 Nov 13. doi: 10.1038/s41423-024-01237-8. Online ahead of print.

Authors

Yunzhu Chen^{1

2}, Baiwen Chen^{1

2}, Jingyu Li^{1

2}, Haixin Li^{1

3}, Gaoyang Wang^{1

2}, Xuemin Cai⁴, Qianqian Zhang^{1

2}, Xiaoxu Liu^{1

2}, Chen Kan⁵, Lei Wang⁶, Zhengting Wang⁷, Hua-Bing Li^{8

9

10

11

12

13}

Affiliations

¹ Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai Jiao Tong University School of Medicine - Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
⁴ Institute of Immunological Innovation & Translation, Chongqing Medical University, Chongqing, China.
⁵ School of Biological Science, The University of Manchester, Manchester, UK.
⁶ Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁸ Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
⁹ Shanghai Jiao Tong University School of Medicine - Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
¹⁰ Institute of Immunological Innovation & Translation, Chongqing Medical University, Chongqing, China. [email protected].
¹¹ Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
¹² Medical Center on Aging, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
¹³ Chongqing International Institute for Immunology, Chongqing, China. [email protected].

PMID: 39537902
DOI: 10.1038/s41423-024-01237-8

Abstract

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.

Keywords: Nudt21; alternative polyadenylation; autophagy; inflammation; macrophage.

Abstract

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