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However, their target proteins and underlying molecular mechanisms remain poorly understood in mycobacteria. Herein, we identified a conserved hypothetical protein Rv1075c, designated MgdE, as a nucleomodulin that enhances mycobacterial intracellular survival. MgdE undergoes nuclear translocation via two nuclear localization signals, KRIR\n                    <jats:sup>108-111<\/jats:sup>\n                    and RLRRPR\n                    <jats:sup>300-305<\/jats:sup>\n                    , and interacts with ASH2L and WDR5, two subunits of the host histone methyltransferase COMPASS complex. This interaction suppresses histone H3 lysine 4 (H3K4) methylation-mediated transcription of pro-inflammatory genes, including\n                    <jats:italic>IL6<\/jats:italic>\n                    and\n                    <jats:italic>IL1\u0392<\/jats:italic>\n                    , thereby promoting mycobacterial survival in both macrophages and mice. Our study provides the first experimental evidence that a bacterial nucleomodulin facilitates intracellular survival by directly targeting the host COMPASS complex. These findings advance our understanding of mycobacterial pathogenesis by revealing a novel mechanism that contributes to its intracellular survival strategy.\n                  <\/jats:p>","DOI":"10.7554\/elife.107677","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T14:30:31Z","timestamp":1755095431000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.107677","source":"Crossref","is-referenced-by-count":2,"title":["A conserved mycobacterial nucleomodulin hijacks the host COMPASS complex to reprogram pro-inflammatory transcription 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 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