The NLRP3 inflammasome senses a range of cellular disturbances, although no consensus exists regarding a common mechanism. Canonical NLRP3 activation is blocked by high extracellular K, regardless of the activating signal. We report here that canonical NLRP3 activation leads to Ca flux and increased calpain activity. Activated calpain releases a pool of Caspase-1 sequestered by the cytoskeleton to regulate NLRP3 activation. Using electrophysiological recording, we found that resting-state eukaryotic membrane potential (MP) is required for this calpain activity, and depolarization by high extracellular K or artificial hyperpolarization results in the inhibition of calpain. Therefore, the MP/Ca/calpain/Caspase-1 axis acts as an independent regulatory mechanism for NLRP3 activity. This finding provides mechanistic insight into high K-mediated inhibition of NLRP3 activation, and it offers an alternative model of NLRP3 inflammasome activation that does not involve K efflux.
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| http://dx.doi.org/10.1016/j.celrep.2018.07.098 | DOI Listing |
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