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

• Published in: Cell death and differentiation Vol. 30; no. 2; pp. 589 - 604
• Main Authors: Bradfield, Clinton J., Liang, Jonathan J., Ernst, Orna, John, Sinu P., Sun, Jing, Ganesan, Sundar, de Jesus, Adriana A., Bryant, Clare E., Goldbach-Mansky, Raphaela, Fraser, Iain D. C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2023; Nature Publishing Group
• Subjects: 13/95; 14/19; 14/33; 14/63; 38/77; 631/250/1932; 631/250/1933; 631/250/256/2515; 631/250/516; 692/699/249; 82/29; 9/10; 96/1; 96/10; 96/106; 96/34; Animal models; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Biosensors; Cell Biology; Cell Cycle Analysis; Colitis; Humans; IL-1β; Inflammasomes; Inflammasomes - metabolism; Inflammatory diseases; Interleukin-1beta - metabolism; Licenses; Life Sciences; Macrophages; Macrophages - metabolism; MAP kinase; MAP Kinase Signaling System; Mice; Mitochondria; Monocytes; Morbidity; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Pyroptosis; Pyroptosis - physiology; Reactive oxygen species; Signal Transduction; Stem Cells; Therapeutic targets; Xanthine oxidase
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-022-01106-9

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.