RBM25 selectively stabilizes XBP1s mRNA independently of splicing factor activity
- 1Uniwersity of Wroclaw
Abstract
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.
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BibTeX
@misc{wiechwalow2026rbm25,
title = {{RBM25 selectively stabilizes XBP1s mRNA independently of splicing factor activity}},
author = {A. Wiech-Walow and A. Barton and M. Tracz and S. Koziol and J. Grzyb and P. Czechowicz and J. F. Collawn and E. Chevet and R. Bartoszewski},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.04.764219},
url = {https://www.biorxiv.org/content/10.64898/2026.11.04.764219v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - RBM25 selectively stabilizes XBP1s mRNA independently of splicing factor activity
AU - A. Wiech-Walow
AU - A. Barton
AU - M. Tracz
AU - S. Koziol
AU - J. Grzyb
AU - P. Czechowicz
AU - J. F. Collawn
AU - E. Chevet
AU - R. Bartoszewski
PY - 2026
DA - 2026/11/04
PB - bioRxiv
DO - 10.64898/2026.11.04.764219
UR - https://www.biorxiv.org/content/10.64898/2026.11.04.764219v1
AB - 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.
ER -