RBM25 selectively stabilizes XBP1s mRNA independently of splicing factor activity

A recently discovered protein, RBM25, plays a crucial role in stabilizing XBP1s mRNA independently of its splicing factor activity. This finding sheds light on a new regulatory checkpoint within the unfolded protein response (UPR), which is vital for maintaining endoplasmic reticulum (ER) proteostasis and preventing cell death during stress.

The IRE1-XBP1 signaling axis, a key component of the UPR, generates the active transcription factor XBP1s through unconventional splicing of XBP1 mRNA. While the mechanisms behind IRE1 activation and XBP1 splicing have been well-studied, the post-transcriptional processes that maintain XBP1s expression are not fully understood. In this study, researchers identified RBM25 as a critical post-transcriptional regulator of the UPR that specifically stabilizes spliced XBP1 mRNA during ER stress.

RBM25 binds to the 3' untranslated region of XBP1s mRNA, extending its half-life without influencing unspliced XBP1u transcripts or IRE1-mediated regulated decay (RIDD) targets. The depletion of RBM25 leads to reduced XBP1 transcriptional output, impaired adaptive UPR signaling, and increased sensitivity to ER stress-induced cell death across various stress conditions.

These results reveal a previously unknown RNA-based regulatory mechanism that amplifies and sustains XBP1 signaling, ultimately fine-tuning the magnitude of the adaptive UPR and cellular survival in response to proteotoxic stress.