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, 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.
Authors
- Xuemin Cai
- Zhengting Wang (ORCID: https://orcid.org/0000-0001-5533-5711)
- Jingyu Li (ORCID: https://orcid.org/0000-0003-3123-6668)
- Qianqian Zhang (ORCID: https://orcid.org/0000-0003-3002-644X)
- Gaoyang Wang (ORCID: https://orcid.org/0000-0003-4742-9886)
- Baiwen Chen (ORCID: https://orcid.org/0000-0002-5370-5544)
- Lei Wang (ORCID: https://orcid.org/0000-0002-1217-2032)
- Yunzhu Chen
- Kan Chen (ORCID: https://orcid.org/0000-0003-4429-9043)
- Xiaoxu Liu (ORCID: https://orcid.org/0000-0001-8268-7077)
- Huabing Li (ORCID: https://orcid.org/0000-0003-3573-6803)
- Haixin Li (ORCID: https://orcid.org/0000-0002-9200-7642)
Institutions
- Tongji University (CN)
- Shanghai Jiao Tong University (CN)
- Ruijin Hospital (CN)
- University of Manchester (GB)
- Sichuan International Studies University (CN)
- Shanghai Tenth People's Hospital (CN)
- State Key Laboratory of Oncogene and Related Genes (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Cellular and Molecular Immunology
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1038/s41423-024-01237-8
- Citations
- 10
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Shanghai Jiao Tong University
- School of Medicine, Shanghai Jiao Tong University