RT Journal Article
SR Electronic
T1 Integrated stress response restricts macrophage necroptosis
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101260
DO 10.26508/lsa.202101260
VO 5
IS 1
A1 David E Place
A1 Parimal Samir
A1 RK Subbarao Malireddi
A1 Thirumala-Devi Kanneganti
YR 2022
UL https://www.life-science-alliance.org/content/5/1/e202101260.abstract
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.