IL10RB-AS1 promotes pro-caspase-1-dependent pyroptosis via regulating the oligomerization and nucleation of CARD8 C-terminal domain to suppress acute myeloid leukemia
5 affiliations
- 1MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- 2Institute of Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Key Laboratory of Big Data Mining and Precision Drug Design, School of Medical Technology, Guangdong Medical University, Dongguan, China
- 3Department of Hepatobiliary, and Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- 4Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- 5Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
Abstract
CARD8 (caspase activation and recruitment domain-containing 8) senses intracellular danger signals, leading to inflammasome formation and pyroptosis. Recently studies have shown that CARD8 was highly expressed in hematopoietic cells, however, the mechanism by which the released C- terminal domain of CARD8 (CARD8-CT) oligomerizes and nucleates, and its role in acute myeloid leukemia (AML) treatment has not been fully understood. Here, we identified a long noncoding RNA IL10RB-AS1 as a novel regulator that can enhance the CARD8-CT oligomer assembly and promote pro-caspase-1-dependent pyroptosis in AML cells. Mechanically, IL10RB-AS1 recruits DEAD-box helicase 3, X-linked (DDX3X) to CARD8 and enhances the DDX3X-CARD8 interaction to promote CARD8-CT nucleation. This process activates the CARD8 inflammasome and triggers an ASC-independent pyroptosis response to perturbations in cellular homeostasis. We found that the C-terminal domain of DDX3X is essential for its interaction with both IL10RB-AS1 and CARD8-CT, facilitating inflammasome activation during AML cell pyroptosis. Importantly, IL10RB-AS1 is highly expressed across AML and correlates with poor outcomes. This elevated expression of IL10RB-AS1 promotes DPP8/9 inhibitor induced pro-caspase-1-dependent pyroptosis in vivo, suggesting that high IL10RB-AS1 levels may predict cellular sensitivity to these inhibitors. Our findings not only reveal a novel mechanism by which a lncRNA orchestrates CARD8-CT nucleation but also highlight new therapeutic opportunities for DPP8/9 inhibitors in hematopoietic malignancies with high IL10RB-AS1 expression.
Related
- ACTB promotes ESCC progression by regulating the AKT–mTOR signaling pathway through an m6A-dependent mechanism
- Ligand identity and oncogenic mutations alter the oligomerization behavior of EGFR: insights from concentration-dependent brightness measurements
- Chronic Intermittent Hypoxia Aggravates the Pyroptosis of Renal Tubular Epithelial Cells Through Regulating Mitophagy‐Mediated NLRP3 Inflammasome Activation
- An N-terminal ATTR Fibril Segment Promotes Transthyretin Amyloid Nucleation and Polymorphism
- IFN-dependent Gsdmd priming induces pyroptosis in coronavirus-infected healthy cells
BibTeX
@article{pan2026il10rbas1,
title = {{IL10RB-AS1 promotes pro-caspase-1-dependent pyroptosis via regulating the oligomerization and nucleation of CARD8 C-terminal domain to suppress acute myeloid leukemia}},
author = {Qi Pan and Bo He and Li-Bin Huang and Qian-Qian Yang and Cheng-Lin Zhou and Yan An and Xin-Yi Feng and Jian-Ping Lian and Shun-Xin Zhu and Ke-Jia Pu and Heng-Jing Huang and Chen Fang and Yi-Xuan Ma and Chang-Hao Liang and Zi-Yuan Wang and Dan Wang and Wei Huang and Yun-Meng Sun and Yue-Qin Chen and Hua Zhang and Wen-Tao Wang},
journal = {Cell Death \& Disease},
year = {2026},
month = jul,
doi = {10.1038/s41419-026-09129-7},
url = {https://doi.org/10.1038/s41419-026-09129-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - IL10RB-AS1 promotes pro-caspase-1-dependent pyroptosis via regulating the oligomerization and nucleation of CARD8 C-terminal domain to suppress acute myeloid leukemia
AU - Qi Pan
AU - Bo He
AU - Li-Bin Huang
AU - Qian-Qian Yang
AU - Cheng-Lin Zhou
AU - Yan An
AU - Xin-Yi Feng
AU - Jian-Ping Lian
AU - Shun-Xin Zhu
AU - Ke-Jia Pu
AU - Heng-Jing Huang
AU - Chen Fang
AU - Yi-Xuan Ma
AU - Chang-Hao Liang
AU - Zi-Yuan Wang
AU - Dan Wang
AU - Wei Huang
AU - Yun-Meng Sun
AU - Yue-Qin Chen
AU - Hua Zhang
AU - Wen-Tao Wang
PY - 2026
DA - 2026/07/31
JO - Cell Death & Disease
DO - 10.1038/s41419-026-09129-7
UR - https://doi.org/10.1038/s41419-026-09129-7
AB - CARD8 (caspase activation and recruitment domain-containing 8) senses intracellular danger signals, leading to inflammasome formation and pyroptosis. Recently studies have shown that CARD8 was highly expressed in hematopoietic cells, however, the mechanism by which the released C- terminal domain of CARD8 (CARD8-CT) oligomerizes and nucleates, and its role in acute myeloid leukemia (AML) treatment has not been fully understood. Here, we identified a long noncoding RNA IL10RB-AS1 as a novel regulator that can enhance the CARD8-CT oligomer assembly and promote pro-caspase-1-dependent pyroptosis in AML cells. Mechanically, IL10RB-AS1 recruits DEAD-box helicase 3, X-linked (DDX3X) to CARD8 and enhances the DDX3X-CARD8 interaction to promote CARD8-CT nucleation. This process activates the CARD8 inflammasome and triggers an ASC-independent pyroptosis response to perturbations in cellular homeostasis. We found that the C-terminal domain of DDX3X is essential for its interaction with both IL10RB-AS1 and CARD8-CT, facilitating inflammasome activation during AML cell pyroptosis. Importantly, IL10RB-AS1 is highly expressed across AML and correlates with poor outcomes. This elevated expression of IL10RB-AS1 promotes DPP8/9 inhibitor induced pro-caspase-1-dependent pyroptosis in vivo, suggesting that high IL10RB-AS1 levels may predict cellular sensitivity to these inhibitors. Our findings not only reveal a novel mechanism by which a lncRNA orchestrates CARD8-CT nucleation but also highlight new therapeutic opportunities for DPP8/9 inhibitors in hematopoietic malignancies with high IL10RB-AS1 expression.
SN - 2041-4889
ER -