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

Cell Death Differ. 2023 Feb;30(2):589-604. doi: 10.1038/s41418-022-01106-9. Epub 2023 Jan 9.

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 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.

MeSH terms

  • Animals
  • Humans
  • Inflammasomes* / metabolism
  • Interleukin-1beta / metabolism
  • MAP Kinase Signaling System
  • Macrophages / metabolism
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Pyroptosis* / physiology
  • Signal Transduction

Substances

  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • MAP kinase kinase kinase 7
  • MAP3K5 protein, human