Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
Life Sci Alliance. 2021 Nov 11;5(1). doi: 10.26508/lsa.202101260. Print 2022 Jan.
The integrated stress response (ISR) regulates cellular homeostasis and cell survival following exposure to stressors. Cell death processes such as apoptosis and pyroptosis are known to be modulated by stress responses, but the role of the ISR in necroptosis is poorly understood. Necroptosis is an inflammatory, lytic form of cell death driven by the RIPK3-MLKL signaling axis. Here, we show that macrophages that have induced the ISR are protected from subsequent necroptosis. Consistent with a reduction in necroptosis, phosphorylation of RIPK1, RIPK3, and MLKL is reduced in macrophages pre-treated with ISR-inducing agents that are challenged with necroptosis-inducing triggers. The stress granule component DDX3X, which is involved in ISR-mediated regulation of pyroptosis, is not required for protecting ISR-treated cells from necroptosis. Disruption of stress granule assembly or knockdown of restored necroptosis in pre-stressed cells. Together, these findings identify a critical role for the ISR in limiting necroptosis in macrophages.
整合应激反应 (ISR) 可调节细胞内环境稳态和细胞在应激源暴露后的存活。已知细胞死亡过程（如细胞凋亡和细胞焦亡）可受到应激反应的调节，但 ISR 在细胞坏死中的作用尚不清楚。细胞坏死是一种由 RIPK3-MLKL 信号轴驱动的炎症性、溶酶体性细胞死亡形式。在这里，我们表明，诱导 ISR 的巨噬细胞可免受随后的细胞坏死。与细胞坏死减少一致，用诱导 ISR 的试剂预处理的巨噬细胞中 RIPK1、RIPK3 和 MLKL 的磷酸化在受到细胞坏死诱导物的挑战时减少。参与 ISR 介导的细胞焦亡调节的应激颗粒成分 DDX3X 对于保护 ISR 处理的细胞免受细胞坏死并不必需。应激颗粒组装的破坏或 的敲低恢复了预应激细胞中的细胞坏死。总之，这些发现确定了 ISR 在限制巨噬细胞中细胞坏死中的关键作用。
