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Spliceosome inhibition generates Z-form RNAs to active ZBP1-mediated 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 generalized mechanisms by which cell sensed and respond to splicing dysregulation remain elusive. Here we show that spliceosome inhibition induces the widespread formation of unique, left-handed nucleic acids, Z-form nucleic acids (Z-NAs) from the nucleus. These Z-NAs were double-stranded RNA (dsRNA) that were predominantly derived from transcripts of mis-spliced intronic RNA. Spliceosome inhibition induced the egress of these Z-RNA from the nucleus to the cytoplasm in an active manner. Sensing of the accumulation of Z-RNA in the cytosol 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: GSE276187 | GEO | 2026/08/01

REPOSITORIES: GEO

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