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Mol Cell. 2017 Oct 5;68(1):185-197.e6. doi: 10.1016/j.molcel.2017.08.017. Epub 2017 Sep 21.

NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation.

Author information

1
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
2
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
3
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China; Collaborative Innovation Center for Biotherapy, China.
4
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; Collaborative Innovation Center for Biotherapy, China.
5
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China; Collaborative Innovation Center for Biotherapy, China. Electronic address: tzhou@ncba.ac.cn.
6
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China; Collaborative Innovation Center for Biotherapy, China. Electronic address: tli@ncba.ac.cn.

Abstract

Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation. We show that NLRP3 inflammasome activation is disrupted in NLRP3-S194A knockin mice. JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. Importantly, we demonstrate that blocking S194 phosphorylation prevents NLRP3 inflammasome activation in cryopyrin-associated periodic syndromes (CAPS). Thus, our study reveals a key priming molecular event that is a prerequisite for NLRP3 inflammasome activation. Inhibiting NLRP3 phosphorylation could be an effective treatment for NLRP3-related diseases.

KEYWORDS:

CAPS; JNK1; NLRP3; inflammasome; phosphorylation; priming

PMID:
28943315
DOI:
10.1016/j.molcel.2017.08.017
[Indexed for MEDLINE]
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