TY - JOUR
T1 - Integrated stress response restricts macrophage necroptosis
AU - Place, David E.
AU - Samir, Parimal
AU - Subbarao Malireddi, R. K.
AU - Kanneganti, Thirumala Devi
N1 - Funding Information:
We thank Drs. Peter Gough and John Bertin for generously providing Ripk1K45A/K45A mice. This work was supported by the National Institutes of Health grants CA253095, AR056296, AI160179, AI124346 and AI101935 and by American Lebanese Syrian Associated Charities to T-D Kanneganti. Microscopy images were acquired at the Cell & Tissue Imaging Center which is supported by St. Jude Children’s Research Hospital and the National Cancer Institute P30 CA021765. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2022 Rockefeller University Press. All rights reserved.
PY - 2022/1
Y1 - 2022/1
N2 - 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 ISRmediated 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.
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 ISRmediated 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.
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U2 - 10.26508/lsa.202101260
DO - 10.26508/lsa.202101260
M3 - Article
C2 - 34764207
AN - SCOPUS:85120748801
SN - 2575-1077
VL - 5
JO - Life Science Alliance
JF - Life Science Alliance
IS - 1
M1 - e202101260
ER -