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ZBP1 Senses Splicing Aberration by Z-RNA for Cell Death

ABSTRACT: RNA splicing, a highly regulated process performed by the spliceosome, is crucial 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 produced by spliceosome aberration and how cell sensed and responded to them remain elusive. Here we show that spliceosome inhibition induces the widespread formation of unique, left-handed nucleic acids, Z-form dsRNA that were predominantly derived from transcripts of exonic and intronic regions of mis-spliced RNA in the nucleus. Then those Z-RNA was translocated into cytoplasm in a RanGTP-dependent manner. Sensing of the accumulation of Z-RNA by the host sensor ZBP1 triggered cell death, mainly for RIPK3-MLKL dependent necroptosis. Collectively, these findings delineate a previously uncharacterized mechanism in which Z-NA sensing by ZBP1 responds to global aberrations of RNA splicing to trigger inflammatory cell death.

ORGANISM(S): Mus musculus

PROVIDER: GSE286049 | GEO | 2026/08/01

REPOSITORIES: GEO

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Spliceosome inhibition generates Z-form RNAs to active ZBP1-mediated cell death

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