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 <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) infection, macrophages enhance FTH1 expression to sequestrate iron and limit <i>Mtb</i> growth. However, <i>Mtb</i> 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 <i>Mtb</i> 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 <i>FTH1</i> expression during <i>Mtb</i> infection. Our study demonstrates that <i>Mtb</i> induces APA of <i>FTH1</i> in macrophages, favoring the production of longer isoforms that enhance protein synthesis. Mechanistically, <i>Mtb</i> disrupts the interaction between NUDT21 and CPSF6, impairing NUDT21's ability to bind UGUA motifs in the <i>FTH1</i> 3'UTR, a key step in polyadenylation site selection. Silencing NUDT21 reduces macrophage bactericidal activity against <i>Mtb</i>, highlighting its role in immune defense. These findings reveal a novel <i>Mtb</i>-driven mechanism that enhances <i>FTH1</i> expression via the NUDT21-mediated APA pathway in macrophages, suggesting that <i>Mtb</i> manipulates this process to promote its survival. This study provides new insights into tuberculosis pathogenesis and points to potential avenues for therapeutic exploration.