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Nucleomodulins, bacterial effectors that target the host cell nuclei, are increasingly recognized as key virulence factors, but their roles in mycobacterial pathogenesis remain incompletely elucidated. Here, we characterize a hypothetical protein Rv2577 (designated MmpE) not only as a Fe\u00b3\n                    <jats:sup>+<\/jats:sup>\n                    \/Zn\u00b2\n                    <jats:sup>+<\/jats:sup>\n                    -dependent metallophosphatase but also as a critical nucleomodulin involved in immune evasion and intracellular persistence. MmpE utilizes two nuclear localization signals, RRR\n                    <jats:sup>20-22<\/jats:sup>\n                    and RRK\n                    <jats:sup>460-462<\/jats:sup>\n                    , to enter the host cell nucleus, where it binds to the promoter region of the vitamin D receptor (VDR) gene, thereby inhibiting host inflammatory gene expression. Additionally, MmpE regulates the PI3K-Akt-mTOR signaling pathway, thereby arresting lysosome maturation. These actions collectively facilitate immune suppression and promote mycobacterial survival in macrophages and in mice. Our findings identify MmpE as a conserved nucleomodulin in mycobacteria and reveal a novel mechanism of MmpE-mediated intracellular survival.\n                  <\/jats:p>","DOI":"10.7554\/elife.108037","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T18:30:56Z","timestamp":1757097056000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.108037","source":"Crossref","is-referenced-by-count":0,"title":["Mycobacterial metallophosphatase MmpE acts as a nucleomodulin to regulate host gene expression and promote intracellular survival"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3722-6994","authenticated-orcid":true,"given":"Liu","family":"Chen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/023b72294","id-type":"ROR","asserted-by":"publisher"}],"name":"National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University","place":["Wuhan, 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