A ZBP1 isoform blocks ZBP1-mediated cell death
Zhi-Yu Cai1, Puqi Wu2, Hao Liang2
1State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou 310012, China.
Cell Reports
|May 15, 2024
Summary
A newly identified ZBP1-S protein isoform suppresses ZBP1-mediated inflammation and cell death. This discovery reveals ZBP1 alternative splicing as a key regulator of inflammatory signaling pathways.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Z-form nucleic acid (Z-NA) sensing by Z-DNA binding protein 1 (ZBP1) triggers inflammatory responses.
- Mechanisms regulating ZBP1 activation and inflammatory signaling require further elucidation.
Purpose of the Study:
- To identify intrinsic mechanisms that dampen ZBP1-mediated inflammation.
- To characterize a novel short isoform of ZBP1 (ZBP1-S) and its role in regulating ZBP1 signaling.
Main Methods:
- Characterization of ZBP1 isoforms and their interaction with Z-NA.
- Analysis of ZBP1-S function in cell death and inflammatory signaling.
- Utilizing mouse models with cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome.
Main Results:
- ZBP1-S acts as an intrinsic suppressor of ZBP1-mediated cell death and inflammation.
- ZBP1-S functions by competitively binding Z-NA, preventing interaction with full-length ZBP1.
- Deletion of ZBP1-S in CRIA syndrome mouse cells leads to spontaneous cell death, highlighting ZBP1-S's regulatory role.
Conclusions:
- Alternative splicing of Zbp1 generates ZBP1-S, providing autogenic inhibition of ZBP1 signaling.
- ZBP1-S is a critical regulator of ZBP1-dependent inflammatory responses.
- Disrupting Z-NA and ZBP1 interaction may offer therapeutic strategies for autoinflammatory diseases.
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