{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:56:16Z","timestamp":1788432976855,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.pbio.3003096","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000}}],"reference-count":79,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T00:00:00Z","timestamp":1744329600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>Multiple myeloma (MM) arises through oncogenic transformation of immunoglobulin-secreting plasma cells. MM often co-opts the central endoplasmic reticulum (ER)-stress mitigator, inositol-requiring enzyme 1 (IRE1), to sustain malignant growth. While certain MMs require enzymatic IRE1-dependent activation of the transcription factor XBP1s, others display a nonenzymatic IRE1 dependency that is not yet mechanistically understood. Here we identify interferon regulatory factor 4 (IRF4), which stimulates genes that promote immune-cell proliferation, as a key conduit for IRE1\u2019s nonenzymatic control of cell-cycle progression in MM. IRE1 silencing increased inhibitory S114\/S270 phosphorylation on IRF4, disrupting IRF4\u2019s chromatin-binding and transcriptional activity. IRF4 knockdown recapitulated, whereas IRF4 repletion reversed, the anti-proliferative phenotype of IRE1 silencing. Furthermore, phospho-deficient, but not phospho-mimetic, IRF4 mutants rescued proliferation under IRE1 silencing. Functional studies revealed that IRF4 engages the <jats:italic>E2F1<\/jats:italic> and <jats:italic>CDC25A<\/jats:italic> genes and promotes CDK2 activation to drive cell-cycle progression. Our results advance mechanistic understanding of IRE1 and IRF4 in MM.<\/jats:p>","DOI":"10.1371\/journal.pbio.3003096","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T17:28:44Z","timestamp":1744392524000},"page":"e3003096","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Interferon regulatory factor 4 mediates nonenzymatic IRE1 dependency in multiple myeloma cells"],"prefix":"10.1371","volume":"23","author":[{"given":"Ioanna","family":"Oikonomidi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasumathi","family":"Kameswaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria 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