Biphasic JNK signaling reveals distinct MAP3K complexes licensing inflammasome formation and pyroptosis
Year: 2023
Type: conference-abstract
Abstract: Kinase signaling in the tiered activation of inflammasomes and associated pyroptosis is a prime therapeutic target for inflammatory diseases. While MAPKs subsume pivotal roles during inflammasome priming, specifically the MAP3K7/JNK1/NLRP3 licensing axis, their involvement in successive steps of inflammasome activation is poorly defined. Using live–cell MAPK biosensors to focus on the inflammasome triggering event allowed us to identify a subsequent biphasic JNK activation. We find that post–trigger JNK signaling distinctly facilitates both mitochondrial reactive oxygen species generation needed to support core inflammasome formation, and gasdermin–mediated cell permeation leading to release of active IL–1β from human macrophages. We further identify and characterize a xanthine oxidase–ROS activated MAP3K5/JNK2 substrate licensing complex as a novel regulator of GSDMD mobilization preceding pyroptosis. We find that inhibitors targeting this MAP3K5 cascade alleviate morbidity in mouse models of colitis and dampen both augmented IL–1β release and cell permeation in monocytes derived from patients with gain–of–function inflammasomopathies. This work was supported by the Intramural Research Program of NIAID, NIH.
Source: The Journal of Immunology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4385685908