{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:32:53Z","timestamp":1789522373084,"version":"build-2803163510"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017607","name":"Shenzhen Municipal Fundamental Research Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017607","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Ferritin heavy chain 1 (FTH1) is a key iron-storage protein that regulates iron availability, supports immune defense, and prevents iron-induced toxicity. During <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>Mtb<\/jats:italic>) infection, macrophages enhance FTH1 expression to sequestrate iron and limit <jats:italic>Mtb<\/jats:italic> growth. However, <jats:italic>Mtb<\/jats:italic> can exploit the host ferritinophagy pathway to degrade FTH1 and release iron, thereby promoting its survival. Although FTH1 plays an essential role in host\u2013pathogen interaction during <jats:italic>Mtb<\/jats:italic> 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\u2019s 3\u2032UTR, may regulate <jats:italic>FTH1<\/jats:italic> expression during <jats:italic>Mtb<\/jats:italic> infection. Our study demonstrates that <jats:italic>Mtb<\/jats:italic> induces APA of <jats:italic>FTH1<\/jats:italic> in macrophages, favoring the production of longer isoforms that enhance protein synthesis. Mechanistically, <jats:italic>Mtb<\/jats:italic> disrupts the interaction between NUDT21 and CPSF6, impairing NUDT21\u2019s ability to bind UGUA motifs in the <jats:italic>FTH1<\/jats:italic> 3\u2032UTR, a key step in polyadenylation site selection. Silencing NUDT21 reduces macrophage bactericidal activity against <jats:italic>Mtb<\/jats:italic>, highlighting its role in immune defense. These findings reveal a novel <jats:italic>Mtb<\/jats:italic>-driven mechanism that enhances <jats:italic>FTH1<\/jats:italic> expression via the NUDT21-mediated APA pathway in macrophages, suggesting that <jats:italic>Mtb<\/jats:italic> manipulates this process to promote its survival. This study provides new insights into tuberculosis pathogenesis and points to potential avenues for therapeutic exploration.<\/jats:p>","DOI":"10.3389\/fcimb.2025.1578163","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:44:55Z","timestamp":1746186295000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Mycobacterium tuberculosis modulates NUDT21-mediated alternative polyadenylation to enhance FTH1 expression in macrophages and promotes intracellular growth"],"prefix":"10.3389","volume":"15","author":[{"given":"Xiaoqian","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningjian","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youchao","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinchun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobin","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.chom.2018.08.002","article-title":"Capsid-CPSF6 interaction licenses nuclear HIV-1 trafficking to sites of viral DNA integration","volume":"24","author":"Achuthan","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.756288","article-title":"Genome-wide profiling reveals alternative polyadenylation of innate immune-related mRNA in patients with COVID-19","volume":"12","author":"An","year":"2021","journal-title":"Front. 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