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

Wang, W.; Hu, D.; Feng, Y.; Wu, C.; Song, Y.; Li, A.; Liu, W.; Wang, Y.; Chen, K.; Tian, M.; Xiao, F.; Zhang, Q.; Chen, W.; Pan, P.; Wan, P.; Liu, Y.; Wu, K.; Wu, J.

doi:10.1101/2020.04.03.023721

bioRxiv · 10.1101/2020.04.03.023721

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

Wang, W.·Hu, D.·Feng, Y.·Wu, C.·Song, Y.·Li, A.·Liu, W.·Wang, Y.·Chen, K.·Tian, M.·Xiao, F.·Zhang, Q.·Chen, W.·Pan, P.·Wan, P.·Liu, Y.·Wu, K.·Wu, J.

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Abstract

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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Wang, W., Hu, D., Feng, Y., Wu, C., Song, Y., Li, A., Liu, W., Wang, Y., Chen, K., Tian, M., Xiao, F., Zhang, Q., Chen, W., Pan, P., Wan, P., Liu, Y., Wu, K., Wu, J.. 2020-04-03. Paxillin Promotes ATP-induced Activation of P2X7 Receptor and NLRP3 Inflammasome. https://doi.org/10.1101/2020.04.03.023721

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