Nudt21 ablation in macrophages induces constitutive autophagy activation and diminishes inflammation in inflammatory diseases

Macrophage hyperactivation is a hallmark of inflammatory diseases, yet the role of alternative polyadenylation (APA) in regulating innate immunity remains unclear. In this study, we demonstrate that Nudt21, a crucial RNA-binding component of the APA machinery, is significantly upregulated in various inflammatory settings. Utilizing myeloid-specific Nudt21-deficient mice, we reveal 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 by mediating selective 3'UTR polyadenylation in activated macrophages. As a result, Nudt21-deficient macrophages display enhanced autophagic activity, which leads to reduced cytokine secretion. Overall design: To identify the potential targets regulated by Nudt21 in inflammatory macrophages, we harvested bone marrow derived macrophages (BMDMs) from WT and Nudt21-cKO mice with and without IFN?/LPS treatment (4hr) for deep RNA sequencing. Bioinformatic analysis revealed that Nudt21 deficiency results in alterations in mRNA levels and 3'UTR lengths of 354 genes, with enrichment observed in autophagy-related pathways.