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Paxillin Promotes ATP-induced Activation of P2X7 Receptor and NLRP3 Inflammasome

By Wenbiao Wang, Dingwen Hu, Yuqian Feng, Caifeng Wu, Yunting Song, Weiyong Liu, Aixin Li, Yingchong Wang, Keli Chen, Mingfu Tian, Feng Xiao, Qi Zhang, Weijie Chen, Pan Pan, Pin Wan, Jianguo Wu, Kailang Wu, Jianguo Wu

Posted 03 Apr 2020
bioRxiv DOI: 10.1101/2020.04.03.023721

The stimulation of P2X7 receptor by extracellular ATP leads to activation of NLRP3 inflammasome and release of pro-inflammatory cytokines. Here, we reveal a distinct mechanism by which Paxillin promotes ATP-induced activation of P2X7 receptor and NLRP3 inflammasome. Extracellular ATP induces Paxillin phosphorylation and facilitates Paxillin-NLRP3 interaction. Interestingly, Paxillin enhances NLRP3 deubiquitination and activates NLRP3 inflammasome upon ATP treatment and K+ efflux. Moreover, we reveal that UPS13 is a key enzyme for Paxillin-mediated NLRP3 deubiquitination upon ATP treatment. Notably, extracellular ATP promotes Paxillin and NLRP3 migration from cytosol to plasma membrane and facilitates P2X7-Paxillin interaction and Paxillin-NLRP3 association, resulting in the formation of P2X7-Paxillin-NLRP3 complex. Functionally, Paxillin is essential for ATP-induced NLRP3 inflammasome activation in mouse BMDMs and BMDCs as we as in human PBMCs and THP-1-differentiated macrophages. Thus, Paxillin plays key roles in ATP-induced activation of P2X7 receptor and NLRP3 inflammasome by facilitating the formation of the P2X7-Paxillin-NLRP3 complex.

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