RBM39 Modulates UPR Signaling Through Regulation of IRE1α Alternative Splicing. Kim and Behera et al.

Description

The unfolded protein response (UPR) maintains endoplasmic reticulum proteostasis through signaling branches, including the IRE1α-XBP1 axis, which promotes cell survival via non-canonical XBP1 splicing. Upstream regulators of this pathway remain incompletely defined. Using CRASP-Seq, a scalable RNA-based CRISPR screening platform, we identified RBM39, a U2 snRNP auxiliary factor, as essential for XBP1 non-canonical splicing. RBM39 perturbation triggers ERN1 exon-18 skipping, destabilizing IRE1α and generating a dominant-negative isoform that impairs XBP1 splicing. Heat shock reduces RBM39 activity and induces ERN1 exon-18 skipping, revealing a stress-responsive mechanism that suppresses the IRE1α-XBP1 axis. These results uncover a previously unrecognized layer of UPR regulation.

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Institutions

• National Cancer Institute

  MD, Bethesda
• National Institutes of Health

  Wilayah Persekutuan, Kuala Lumpur
• Center for Cancer Research

  MD, Bethesda

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