2. Academic Validation
  3. Telomeric repeat-containing RNA G-quadruplexes trigger ZBP1-mediated cell death

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

  • Nat Commun. 2026 Feb 23;17(1):3076. doi: 10.1038/s41467-026-69989-7.
Geng Qin # 1 2 3,  Chuanqi Zhao # 1 2,  Chengming Gao 4,  Wenxuan Hu 5,  Na Zhang 5,  Jinsong Ren 1 2,  Xiaogang Qu 6 7
Affiliations

Affiliations

  • 1 Laboratory 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.
  • 2 University of Science and Technology of China, Hefei, Anhui, PR China.
  • 3 Cancer Institute, First Hospital of Jilin University, Changchun, PR China.
  • 4 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, PR China.
  • 5 High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, PR China.
  • 6 Laboratory 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. [email protected].
  • 7 University of Science and Technology of China, Hefei, Anhui, PR China. [email protected].
  • # Contributed equally.
PMID: 41730904 DOI: 10.1038/s41467-026-69989-7
Abstract

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.

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