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 demon...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.展开更多
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.).
文摘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.
