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

Geng Qin1,2,3, Chuanqi Zhao1,2, Chengming Gao4

  • 1Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, PR China.

Nature Communications
|February 23, 2026
PubMed

Insights

Z-DNA-binding protein 1-S (ZBP1-S) senses G-quadruplexes in telomeric repeat-containing RNA (TERRA), triggering inflammatory cell death. G4-specific ligands block this interaction, inhibiting ZBP1-S-mediated immune signaling.

Area of Science:

  • Molecular Biology
  • Immunology
  • Genetics

Background:

  • Z-DNA-binding protein 1 (ZBP1) is a nucleic acid sensor involved in inflammatory cell death.
  • The truncated ZBP1-S isoform senses telomeric repeat-containing RNA (TERRA), activating innate immunity.
  • The exact mechanism of ZBP1-S sensing of TERRA is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which ZBP1-S senses TERRA.
  • To investigate the role of G-quadruplexes (G4s) in ZBP1-S activation.
  • To explore potential therapeutic strategies targeting the ZBP1-S-TERRA interaction.

Main Methods:

  • Biochemical assays to demonstrate direct binding of ZBP1-S to TERRA G4 structures.
  • Oligomerization assays to assess ZBP1-S conformational changes upon G4 binding.
  • Interferon signaling pathway activation assays in response to ZBP1-S and TERRA G4s.
  • Inhibition studies using G4-specific ligands to block ZBP1-S-TERRA interaction.

Main Results:

  • ZBP1-S directly binds to G-quadruplex structures within TERRA.
  • Binding of TERRA G4s induces ZBP1-S oligomerization.
  • ZBP1-S oligomerization leads to the induction of inflammatory cell death.
  • G4-specific ligands effectively compete with ZBP1-S for TERRA binding and inhibit ZBP1-S-mediated interferon signaling.

Conclusions:

  • ZBP1-S recognizes and binds to G-quadruplex structures in TERRA as the primary sensing mechanism.
  • This interaction triggers ZBP1-S oligomerization and subsequent inflammatory cell death.
  • Targeting TERRA G4s with specific ligands offers a potential therapeutic approach to modulate ZBP1-S-driven inflammation.

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