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Published on: July 6, 2021
Synthetic protein circuits for programmable control of mammalian cell death
Shiyu Xia1, Andrew C Lu2, Victoria Tobin3
1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
Abstract:
Natural cell death pathways such as apoptosis and pyroptosis play dual roles: they eliminate harmful cells and modulate the immune system by dampening or stimulating inflammation. Synthetic protein circuits capable of triggering specific death programs in target cells could similarly remove harmful cells while appropriately modulating immune responses. However, cells actively influence their death modes in response to natural signals, making it challenging to control death modes. Here, we introduce naturally inspired "synpoptosis" circuits that proteolytically regulate engineered executioner proteins and mammalian cell death. These circuits direct cell death modes, respond to combinations of protease inputs, and selectively eliminate target cells. Furthermore, synpoptosis circuits can be transmitted intercellularly, offering a foundation for engineering synthetic killer cells that induce desired death programs in target cells without self-destruction. Together, these results lay the groundwork for programmable control of mammalian cell death.
Insights
Scientists engineered synthetic cell death circuits, called synpoptosis, to precisely control how cells die and modulate immune responses. These programmable circuits offer a new way to eliminate harmful cells without harming healthy ones.
Area of Science:
- Synthetic biology
- Cellular biology
- Immunology
Background:
- Natural cell death pathways like apoptosis and pyroptosis have dual roles in eliminating harmful cells and modulating immune responses.
- Controlling specific cell death modes is challenging due to cellular responses to natural signals.
Purpose of the Study:
- To engineer synthetic protein circuits, termed "synpoptosis" circuits, for programmable control of mammalian cell death.
- To develop circuits that can selectively eliminate target cells and modulate immune responses.
Main Methods:
- Designed synpoptosis circuits that proteolytically regulate engineered executioner proteins to trigger specific cell death programs.
- Investigated the ability of these circuits to respond to protease inputs and direct cell death modes.
- Examined the intercellular transmission of synpoptosis circuits.
Main Results:
- Synpoptosis circuits successfully directed specific mammalian cell death modes.
- The circuits responded to combinations of protease inputs, enabling selective target cell elimination.
- Engineered circuits demonstrated intercellular transmission, allowing for the creation of synthetic killer cells.
Conclusions:
- Synpoptosis circuits provide a foundation for programmable control over mammalian cell death.
- These synthetic circuits offer a novel approach for targeted cell elimination and immune response modulation.
- The development of synpoptosis circuits paves the way for engineering synthetic killer cells without self-destruction.
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