Biphasic JNK signaling reveals distinct MAP3K complexes licensing inflammasome formation and pyroptosis

Clinton J. Bradfield, Jonathan J. Liang, Orna Ernst, Sinu P. John, Jing Sun, Sundar Ganesan, Adriana A. de Jesus, Clare E. Bryant, Raphaela Goldbach-Mansky, Iain D.C. Fraser

Research output: Contribution to journalArticlepeer-review


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 process of biphasic JNK activation. We find that this biphasic post-trigger JNK signaling initially facilitates the mitochondrial reactive oxygen species generation needed to support core inflammasome formation, then supports the gasdermin-mediated cell permeation required for 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 the GSDMD mobilization which precedes pyroptosis. We show 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.

Original languageEnglish (US)
Pages (from-to)589-604
Number of pages16
JournalCell death and differentiation
Issue number2
StatePublished - Feb 2023
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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