Wiech-Walow, A.; Barton, A.; Tracz, M.; Koziol, S.; Grzyb, J.; Czechowicz, P.; Collawn, J. F.; Chevet, E.; Bartoszewski, R.

The unfolded protein response (UPR) preserves endoplasmic reticulum (ER) proteostasis through coordinated transcriptional and translational programs that promote adaptation and prevents apoptosis. A central component of this response is the IRE1-XBP1 signaling axis, in which IRE1-mediated unconventional splicing of XBP1 mRNA generates the active transcription factor XBP1s. While the mechanisms governing IRE1 activation and XBP1 splicing have been extensively characterized, the post-transcriptional processes that sustain XBP1s expression remain poorly understood. Here, we identify RNA-binding motif protein 25 (RBM25) as a key post-transcriptional regulator of the UPR that selectively stabilizes spliced XBP1 mRNA during ER stress. RBM25 binds the XBP1s 3' untranslated region and prolongs XBP1s mRNA half-life without affecting unspliced XBP1u transcripts or IRE1-dependent regulated decay (RIDD) targets. Consequently, RBM25 depletion diminishes XBP1 transcriptional output, compromises adaptive UPR signaling, and sensitizes cells to ER stress-induced death across multiple stress paradigms. Together, our findings uncover a previously unrecognized RNA-based regulatory checkpoint that amplifies and sustains XBP1 signaling, thereby tuning the magnitude of the adaptive UPR and cellular survival under proteotoxic stress.