{"database":"GEO","file_versions":[],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312843"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"RBM39 Modulates UPR Signaling Through Alternative Splicing of IRE1α/ERN1 [Spliceosome_Inhibition_RNA-Seq]","description":"The unfolded protein response (UPR) preserves endoplasmic reticulum proteostasis through coordinated signaling pathways, including the IRE1α-XBP1 axis, which promotes adaptive transcriptional programs via non-canonical XBP1 mRNA splicing. However, upstream mechanisms regulating this pathway remain incompletely defined. Here, we apply CRASP-Seq, a scalable RNA-coupled CRISPR screening platform, to systematically identify regulators of XBP1 splicing. We uncover the U2 snRNP auxiliary factor RBM39 as a critical positive regulator of this process. Perturbation of RBM39 or U2 snRNP components induces alternative splicing of ERN1, leading to exon-18 skipping and the production of an unstable transcript subject to nonsense-mediated decay, as well as a truncated IRE1α isoform that acts in a dominant-negative manner to suppress XBP1 splicing. Mechanistically, we show that heat shock reduces RBM39 functional activity and promotes ERN1 exon-18 skipping, thereby attenuating IRE1α–XBP1 signaling. Functionally, hyperactivation of this pathway is detrimental under proteotoxic stress, suggesting that exon-18 skipping serves as a stress-adaptive mechanism to limit UPR output. Together, our findings reveal a previously unrecognized regulatory axis linking the canonical splicing machinery to UPR signaling and establish alternative splicing of ERN1 as a key modulator of cellular stress responses.","dates":{"publication":"2026/04/27"},"accession":"GSE312843","cross_references":{"GSM":["GSM9355353","GSM9355364","GSM9355365","GSM9355354","GSM9355362","GSM9355363","GSM9355352","GSM9355360","GSM9355371","GSM9355361","GSM9355370","GSM9355359","GSM9355368","GSM9355357","GSM9355358","GSM9355369","GSM9355355","GSM9355366","GSM9355367","GSM9355356"],"GPL":["34284"],"GSE":["312843"],"taxon":["Homo sapiens"]}}