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. 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 IFNγ/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.