Alternative mRNA polyadenylation regulates macrophage hyperactivation via the autophagy pathway  

作　　者：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 

机构地区：[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]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 [9]Chongqing International Institute for Immunology,Chongqing,China

出　　处：《Cellular & Molecular Immunology》2024年第12期1522-1534,共13页中国免疫学杂志(英文版)

基　　金：supported by the National Natural Science Foundation of China(No.82325024,82341017,82350112,82030042 and 32070917 to H.-B.L.);the Ministry of Science and Technology of China(No.2021YFA1100800 to H.-B.L.);the Shanghai Municipal Health Commission(No.2022XD047 and 2022JC001 to H.-B.L.).

摘　　要：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.

关 键 词：alternative polyadenylation Nudt21 MACROPHAGE AUTOPHAGY INFLAMMATION 

分 类 号：R392[医药卫生—免疫学]