Synthetic protein circuits for programmable control of mammalian cell death

Shiyu Xia; Andrew C Lu; Victoria Tobin; Kaiwen Luo; Lukas Moeller; D Judy Shon; Rongrong Du; James M Linton; Margaret Sui; Felix Horns; Michael B Elowitz

doi:10.1016/j.cell.2024.03.031

Synthetic protein circuits for programmable control of mammalian cell death

Cell. 2024 Apr 16:S0092-8674(24)00347-7. doi: 10.1016/j.cell.2024.03.031. Online ahead of print.

Authors

Affiliations

¹ Division 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.
² Division 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; UCLA-Caltech Medical Scientist Training Program, University of California, Los Angeles, CA 90095, USA.
³ Division 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; UC Davis-Caltech Veterinary Scientist Training Program, University of California, Davis, CA 95616, USA.
⁴ Division 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. Electronic address: melowitz@caltech.edu.

PMID: 38657604
DOI: 10.1016/j.cell.2024.03.031

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.

Keywords: apoptosis; cell death; protein circuit; pyroptosis; synpoptosis; synthetic biology; synthetic circuit.