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

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

  • Biochem Pharmacol. 2024 Oct 11;230(Pt 1):116572. doi: 10.1016/j.bcp.2024.116572.
Hanwen Chen 1,  Shujun Xie 2,  Yichen Zhou 3,  Lin Chen 4,  Jian Xu 5,  Jianting Cai 6
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, PR China.
  • 2 Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, 310006, PR China.
  • 3 MOA Key Laboratory of Animal Virology, Center for Veterinary Sciences, Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China.
  • 4 Department of General Practice, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, PR China.
  • 5 Department of Central Laboratory, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, PR China.
  • 6 Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, PR China. Electronic address: jtcai6757@zju.edu.cn.
PMID: 39396647 DOI: 10.1016/j.bcp.2024.116572
Abstract

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.

Keywords

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

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