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Bioorthogonally Activatable Base Editing for On-Demand Pyroptosis
William Shu Ching Ngai1,2, Shaojun Yang1, Xiangmei Zeng1,3
1Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Researchers developed a Bioorthogonally ACtivatable Base editor (BaseBAC) to precisely trigger pyroptosis, a form of inflammatory cell death. This new tool enables on-demand initiation of pyroptosis in specific cell types for advanced biological research.
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- Pyroptosis is a programmed inflammatory cell death pathway.
- It is activated by gasdermin (GSDM) protein cleavage.
- Current methods for pyroptosis induction lack precise control.
Purpose of the Study:
- To develop a novel tool for initiating pyroptosis in a controlled manner.
- To enable cell-type-specific induction of pyroptosis.
- To investigate the potential of bioorthogonal chemistry in controlling cellular processes.
Main Methods:
- Engineered a cytosine base editor (CBE) with a bioorthogonal blockage on the PAM-interacting residue.
- Created a Bioorthogonally ACtivatable Base editor (BaseBAC).
- Utilized BaseBAC for targeted base editing of the GSDME gene.
Main Results:
- BaseBAC demonstrated switchable enzymatic activity and controlled DNA binding.
- Achieved precise, on-demand initiation of pyroptosis via GSDME gene editing.
- Showcased cell-type-specific activation of pyroptosis in living systems.
Conclusions:
- BaseBAC provides a generalizable method for controlling gene editing and cellular processes.
- This technology allows for the on-demand activation of self-inhibiting protein domains.
- Offers high specificity for initiating pyroptosis in biological research.
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