Tyrosine phosphatase SHP2-mediated mitochondrial homeostasis for the resolution of inflammation

Abstract

The negative regulation of inflammation is very important for the resolution of inflammatory diseases. Although many components and mediators in inflammation have been identified, how the inflammatory process is finely regulated remains lack of evidence. Here we show that Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) translocates to mitochondria in the early time of inflammatory stimulation. The RRWFH motif in SH2 domain as the mitochondria-targeting sequence is essential for the translocation of SHP2. This phosphatase finally localizes in the mitochondrial matrix with the help of Tom20/Tom40 in the outer membrane and Tim23 in the inner membrane. Then SHP2 interacts with and dephosphorylates 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-1beta 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 for the mitochondrial homeostasis to limit excessive NLRP3 inflammasome activation.

This study is supported by National Natural Science Foundation of China (81330079 and 81730100).