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Human adenovirus (AdV) preferentially activates the IRE1a-XBP1 pathway through the viral membrane protein E3-19K, yet the mechanisms underlying this selective activation remain unclear. Here, we show that AdV uses two distinct early proteins to dissociate BiP from IRE1a and activate IRE1a-mediated XBP1 splicing. The immediate early protein E1A forms a complex with the cytoplasmic domain of IRE1a, sufficient to dissociate BiP from IRE1a without inducing XBP1 splicing or UPR activation. In contrast, E3-19K is expressed downstream of E1A, associates with the lumenal domain of IRE1a, and induces XBP1 splicing without promoting BiP dissociation from IRE1a. Both proteins were detected in IRE1a-containing complexes, consistent with stepwise viral regulation. Together, our findings show that canonical IRE1a activation hallmarks can be mechanistically separated during viral infection, revealing distinct AdV-regulated IRE1a activation states with discrete upstream and downstream signaling outputs.<\/jats:p>","DOI":"10.1091\/mbc.e26-06-0273","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T14:58:11Z","timestamp":1790261891000},"source":"Crossref","is-referenced-by-count":0,"title":["Adenovirus early proteins E1A and E3-19K reveal separable regulatory states of the ER stress sensor IRE1a"],"prefix":"10.1091","volume":"37","author":[{"given":"Debkanya","family":"Sengupta","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shikha","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Heidelberg 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