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Whether mRNA from distant genes can undergo\n                    <jats:italic>trans<\/jats:italic>\n                    -splicing to generate functionally relevant chimeric transcripts has remained unclear. Here we develop a pipeline combining long-read direct RNA sequencing with non-targeted and targeted validation to identify chimeric transcripts in macrophages. Chromatin conformation capture studies reveal that inflammation induces interchromosomal DNA interactions, positioning parent genes proximally to facilitate the formation of chimeric mRNA. Notably, we identify a protein-coding chimeric mRNA representing a fusion between the pore-forming protein gasdermin D (GSDMD)\n                    <jats:sup>1,2<\/jats:sup>\n                    and a C-terminal domain translated out of frame from\n                    <jats:italic>Tmem106a<\/jats:italic>\n                    (\n                    <jats:italic>Gsdmd<\/jats:italic>\n                    -\n                    <jats:italic>Tmem106a<\/jats:italic>\n                    ) in mice. We show that inflammasome priming upregulates\n                    <jats:italic>Gsdmd<\/jats:italic>\n                    -\n                    <jats:italic>Tmem106a<\/jats:italic>\n                    , with the protein localizing to the plasma membrane. After activation of the inflammasome, GSDMD\u2013TMEM106A directly interacts with canonical GSDMD N termini to accelerate and enhance pore formation and IL-1\u03b2 release. Finally, we show that GSDMD\u2013TMEM106A balances host defence and immunopathology in vivo: its loss protects against lethal sepsis but compromises antibacterial defence, whereas overexpression enhances host protection while increasing sepsis lethality. We establish that protein-coding chimeric mRNAs formed by regulated transcript fusion events are operative during inflammation and immunity.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10982-x","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T16:21:28Z","timestamp":1788366088000},"page":"1015-1024","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Functional chimeric mRNAs encode proteins in mammalian immunity"],"prefix":"10.1038","volume":"658","author":[{"given":"Olivia","family":"Venezia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Kane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah 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