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

Wenjie Guo, Wen Liu, Zhen Chen, Yanhong Gu, Shuang Peng, Lihong Shen, Yan Shen, Xingqi Wang, Gen-Sheng Feng, Yang Sun () and Qiang Xu ()
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Wenjie Guo: Nanjing University
Wen Liu: Nanjing University
Zhen Chen: Beckman Research Institute of City of Hope
Yanhong Gu: The First Affiliated Hospital with Nanjing Medical University
Shuang Peng: Nanjing University
Lihong Shen: Nanjing University
Yan Shen: Nanjing University
Xingqi Wang: Nanjing University
Gen-Sheng Feng: University of California San Diego
Yang Sun: Nanjing University
Qiang Xu: Nanjing University

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02351-0

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