ZBP1 senses splicing aberration through Z-RNA to promote cell death

Abstract

RNA splicing, a highly regulated process performed by the spliceosome, is essential for eukaryotic gene expression and cellular function. Numerous cellular stresses, including oncogenic insults, dysregulate RNA splicing, often provoking inflammatory responses and cell death. However, the molecular signals generated by splicing aberrations and the mechanism by which cells sense and respond to these signals remain poorly understood. Here, we demonstrate that spliceosome inhibition induces the widespread formation of left-handed Z-form double-stranded RNA (Z-RNA), predominantly derived from mis-spliced exonic and intronic RNA transcripts in the nucleus. These Z-RNAs are exported to the cytoplasm in a RanGTP-dependent manner. Cytosolic sensing of accumulated Z-RNA by the host sensor Z-DNA-binding protein 1 (ZBP1) initiates cell death, primarily through RIPK3-MLKL-dependent necroptosis. Together, these findings reveal a previously uncharacterized mechanism in which ZBP1-mediated detection of Z-RNA serves as a critical response to global RNA splicing perturbations, ultimately triggering inflammatory cell death.