Telomeric repeat-containing RNA G-quadruplexes trigger ZBP1-mediated cell death

Z-DNA-binding protein 1 (ZBP1) is a nucleic acid sensor with two Z-DNA-binding domains (Zα domains) that bind Z-DNA and Z-RNA, mediating inflammatory cell death in development and disease. A recent study has demonstrated that the truncated isoform ZBP1-S senses telomeric repeat-containing RNA (TERRA), activating innate immune signaling and triggering cell death. However, the precise mechanism on how ZBP1-S senses TERRA remains unknown. G-quadruplexes (G4s) are non-canonical secondary structures of nucleic acids that can form within guanine (G)-rich strands of DNA or RNA, including TERRA. Here, we demonstrate that ZBP1-S directly senses G4 structures within TERRA, leading to ZBP1-S oligomerization and subsequent induction of inflammatory cell death. Furthermore, G4-specific binding ligands can compete with ZBP1-S for binding to TERRA G4s and inhibit ZBP1-S mediated activation of interferon signaling. Therefore, this work deciphers a hitherto uncharacterized mechanism that links TERRA G4s with ZBP1-S activity in triggering inflammatory cell death.