PT  - JOURNAL ARTICLE
AU  - David E Place
AU  - Parimal Samir
AU  - RK Subbarao Malireddi
AU  - Thirumala-Devi Kanneganti
TI  - Integrated stress response restricts macrophage necroptosis
AID  - 10.26508/lsa.202101260
DP  - 2022 Jan 01
TA  - Life Science Alliance
PG  - e202101260
VI  - 5
IP  - 1
4099  - https://www.life-science-alliance.org/content/5/1/e202101260.short
4100  - https://www.life-science-alliance.org/content/5/1/e202101260.full
SO  - Life Sci. Alliance2022 Jan 01; 5
AB  - 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 Perk restored necroptosis in pre-stressed cells. Together, these findings identify a critical role for the ISR in limiting necroptosis in macrophages.