Institute of Innate Immunity, University Hospital Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
Department of Immunobiology, University of Lausanne, Switzerland.
Semin Cell Dev Biol. 2024 Mar 15;156:74-92. doi: 10.1016/j.semcdb.2023.07.012. Epub 2023 Aug 17.
Regulated cell death (RCD) controls the removal of dispensable, infected or malignant cells, and is thus essential for development, homeostasis and immunity of multicellular organisms. Over the last years different forms of RCD have been described (among them apoptosis, necroptosis, pyroptosis and ferroptosis), and the cellular signaling pathways that control their induction and execution have been characterized at the molecular level. It has also become apparent that different forms of RCD differ in their capacity to elicit inflammation or an immune response, and that RCD pathways show a remarkable plasticity. Biochemical and genetic studies revealed that inhibition of a given pathway often results in the activation of back-up cell death mechanisms, highlighting close interconnectivity based on shared signaling components and the assembly of multivalent signaling platforms that can initiate different forms of RCD. Due to this interconnectivity and the pleiotropic effects of 'classical' cell death inducers, it is challenging to study RCD pathways in isolation. This has led to the development of tools based on synthetic biology that allow the targeted induction of RCD using chemogenetic or optogenetic methods. Here we discuss recent advances in the development of such toolset, highlighting their advantages and limitations, and their application for the study of RCD in cells and animals.
细胞程序性死亡（RCD）控制着多余的、感染的或恶性细胞的清除，因此对多细胞生物的发育、稳态和免疫至关重要。在过去的几年中，已经描述了不同形式的 RCD（包括细胞凋亡、细胞坏死性凋亡、细胞焦亡和铁死亡），并且已经在分子水平上描述了控制其诱导和执行的细胞信号通路。不同形式的 RCD 在引发炎症或免疫反应的能力上也存在差异，而且 RCD 途径具有显著的可塑性，这一点也变得显而易见。生化和遗传学研究表明，抑制特定途径通常会导致备用细胞死亡机制的激活，这突出了基于共享信号成分的紧密相互连接性和能够引发不同形式 RCD 的多价信号平台的组装。由于这种相互连接性和“经典”细胞死亡诱导剂的多效性效应，单独研究 RCD 途径具有挑战性。这导致了基于合成生物学的工具的开发，这些工具允许使用化学遗传学或光遗传学方法靶向诱导 RCD。在这里，我们讨论了此类工具集的最新进展，突出了它们的优点和局限性，以及它们在细胞和动物中 RCD 研究中的应用。
