美国加州理工学院Michael B. Elowitz小组报道了，可编程控制哺乳动物细胞死亡的合成蛋白质回路。这一研究成果发表在2024年4月23日出版的国际学术期刊《细胞》上。

研究人员受自然启发研发了"同步凋亡"回路，它通过蛋白水解来调节工程死亡启动蛋白和哺乳动物细胞的死亡。这些回路可引导细胞死亡模式，对蛋白酶输入的组合做出反应，并选择性地消灭靶细胞。

此外，同步凋亡回路还能在细胞间传播，为工程化合成杀伤细胞提供了基础，这些细胞能在靶细胞中诱导所需的死亡程序，而不会自我毁灭。该研究结果为哺乳动物细胞死亡的可编程调控奠定了基础。

研究人员表示，细胞凋亡和裂解等天然细胞死亡途径具有双重作用：它们既能清除有害细胞，又能通过抑制或刺激炎症来调节免疫系统。能够在靶细胞中触发特定死亡程序的合成蛋白质回路，同样具有清除有害细胞以及适当调节免疫反应的功能。然而，细胞会主动影响它们的死亡模式，以响应自然信号，因此对死亡模式的调控具有一定挑战性。

附：英文原文

Title: Synthetic protein circuits for programmable control of mammalian cell death

Author: 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

Issue&Volume: 2024-04-23

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.

DOI: 10.1016/j.cell.2024.03.031

Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00347-7