{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:02:50Z","timestamp":1790085770162,"version":"4.0.1"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Ubiquitin-like modifier activating enzyme 1 (UBA1) occupies the apex of the canonical ubiquitination cascade and supplies activated ubiquitin to a broad network of E2 conjugating enzymes and E3 ligases. Although traditionally regarded as an essential housekeeping enzyme, human genetics has revealed a more instructive function for UBA1: it determines whether proteostatic stress is buffered, converted into inflammatory adaptation, or progresses to cell death. Somatic UBA1 mutations causing VEXAS syndrome provide a natural experiment in this threshold biology. Partial and compartment-selective loss of UBA1 activity permits hematopoietic cells to survive while reducing ubiquitination capacity, activating stress-response pathways, altering cell-death thresholds, and promoting innate immune dysregulation. Single-cell and functional studies further demonstrate early inflammatory activation in UBA1-mutant hematopoietic progenitors, myeloid-biased differentiation, monocyte dysfunction, and inflammasome-associated signaling. Conversely, profound pharmacological UBA1 inhibition with agents such as TAK-243 drives proteotoxic collapse and is being explored as an anticancer strategy. Here, we propose that UBA1 functions as a proteostasis-innate immunity checkpoint whose biological output is determined by residual enzymatic activity, subcellular distribution, lineage context, and clone size. This framework reconciles inflammatory disease caused by partial UBA1 dysfunction with the antitumor effects of UBA1 inhibition and suggests a mechanism-based approach to therapeutic intervention in VEXAS syndrome and malignancy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1974344","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:23:07Z","timestamp":1790083387000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["UBA1 as a proteostasis-innate immunity checkpoint: lessons from vexas syndrome and therapeutic implications"],"prefix":"10.3389","volume":"17","author":[{"given":"Yanyu","family":"Zhang","sequence":"first","affiliation":[{"name":"First Affiliated Hospital, Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanxin","family":"Su","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital, Dalian 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