Mycobacterium tuberculosis modulates NUDT21-mediated alternative polyadenylation to enhance FTH1 expression in macrophages and promotes intracellular growth.

Ferritin heavy chain 1 (FTH1) is a key iron-storage protein that regulates iron availability, supports immune defense, and prevents iron-induced toxicity. During () infection, macrophages enhance FTH1 expression to sequestrate iron and limit growth. However, can exploit the host ferritinophagy pathway to degrade FTH1 and release iron, thereby promoting its survival. Although FTH1 plays an essential role in host-pathogen interaction during infection, its regulation remains unclear. Previous studies suggest that post-transcriptional mechanism, particularly alternative polyadenylation (APA), are critical in immune responses. We propose that APA, which determines the length of a transcript's 3'UTR, may regulate expression during infection. Our study demonstrates that induces APA of in macrophages, favoring the production of longer isoforms that enhance protein synthesis. Mechanistically, disrupts the interaction between NUDT21 and CPSF6, impairing NUDT21's ability to bind UGUA motifs in the 3'UTR, a key step in polyadenylation site selection. Silencing NUDT21 reduces macrophage bactericidal activity against , highlighting its role in immune defense. These findings reveal a novel -driven mechanism that enhances expression via the NUDT21-mediated APA pathway in macrophages, suggesting that manipulates this process to promote its survival. This study provides new insights into tuberculosis pathogenesis and points to potential avenues for therapeutic exploration.