MEK1/2 promote ROS production and deubiquitinate NLRP3 independent of ERK1/2 during NLRP3 inflammasome activation.

Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE

Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.

NLR Family, Pyrin Domain-Containing 3 Protein*/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein*/genetics ; Reactive Oxygen Species*/metabolism ; Inflammasomes*/metabolism ; Ubiquitination*/drug effects ; Ubiquitination*/physiology ; MAP Kinase Kinase 1*/metabolism ; MAP Kinase Kinase 1*/antagonists & inhibitors ; Mice, Inbred C57BL*; Humans ; Animals ; Mice ; MAP Kinase Kinase 2/metabolism ; MAP Kinase Kinase 2/antagonists & inhibitors ; HEK293 Cells ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 1/genetics ; Mitogen-Activated Protein Kinase 1/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinase 3/genetics ; MAP Kinase Signaling System/drug effects ; MAP Kinase Signaling System/physiology ; Male

Inflammasomes are cytosolic supramolecular complexes that play a key role in the innate immune response. Overactivation of NLR family pyrin domain containing 3 (NLRP3) inflammasome leads to multiple diseases. Post-translational modifications (PTMs) are essential modulators of inflammasomes especially in activation phase. Here we found that MEK1/2 kinase activity was indispensable in NLRP3 inflammasome activation both in vitro and in vivo. Inhibition of MEK1/2 resulted in reactive oxygen species (ROS) scavenging and ubiquitination of NLRP3, which further blocked NLRP3 inflammasome activation. These effects were independent of ERK1/2, which were classic downstream of MEK1/2. These investigations proposed a mechanism that MEK1/2 regulated inflammation via non-transcriptional regulation of NLRP3 inflammasome and might help better understanding the effects and side-effects of MEK inhibitors in clinical use.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)

Keywords: MEK inhibitors; MEK1/2; NLRP3 inflammasome; Post-translational modification

0 (NLR Family, Pyrin Domain-Containing 3 Protein)
0 (Reactive Oxygen Species)
0 (Inflammasomes)
EC 2.7.12.2 (MAP Kinase Kinase 1)
EC 2.7.12.2 (MAP Kinase Kinase 2)
0 (Nlrp3 protein, mouse)
0 (NLRP3 protein, human)
EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
EC 2.7.12.2 (MAP2K1 protein, human)
EC 2.7.1.- (MAP2K2 protein, human)
EC 2.7.11.24 (Mapk3 protein, mouse)

Date Created: 20241013 Date Completed: 20241130 Latest Revision: 20241130

20241202

10.1016/j.bcp.2024.116572

39396647