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Nat Commun. 2017 Dec 18;8(1):2168. doi: 10.1038/s41467-017-02351-0.

Tyrosine phosphatase SHP2 negatively regulates NLRP3 inflammasome activation via ANT1-dependent mitochondrial homeostasis.

Author information

1
State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
2
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
3
Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
4
Department of Pathology, and Division of Biological Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
5
State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing, 210023, China. yangsun@nju.edu.cn.
6
State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing, 210023, China. molpharm@163.com.

Abstract

Aberrant activation of NLRP3 inflammasome has an important function in the pathogenesis of various inflammatory diseases. Although many components and mediators of inflammasome activation have been identified, how NLRP3 inflammasome is regulated to prevent excessive inflammation is unclear. Here we show NLRP3 inflammasome stimulators trigger Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) translocation to the mitochondria, to interact with and dephosphorylate adenine nucleotide translocase 1 (ANT1), a central molecule controlling mitochondrial permeability transition. This mechanism prevents collapse of mitochondrial membrane potential and the subsequent release of mitochondrial DNA and reactive oxygen species, thus preventing hyperactivation of NLRP3 inflammasome. Ablation or inhibition of SHP2 in macrophages causes intensified NLRP3 activation, overproduction of proinflammatory cytokines IL-1β and IL-18, and increased sensitivity to peritonitis. Collectively, our data highlight that, by inhibiting ANT1 and mitochondrial dysfunction, SHP2 orchestrates an intrinsic regulatory loop to limit excessive NLRP3 inflammasome activation.

PMID:
29255148
PMCID:
PMC5735095
DOI:
10.1038/s41467-017-02351-0
[Indexed for MEDLINE]
Free PMC Article

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