A Membrane Potential- and Calpain-Dependent Reversal of Caspase-1 Inhibition Regulates Canonical NLRP3 Inflammasome

Cell Rep. 2018 Aug 28;24(9):2356-2369.e5. doi: 10.1016/j.celrep.2018.07.098.

Abstract

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 Ca2+ 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/Ca2+/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.

Keywords: Calpain; NLRP3 inflammasome; caspase-1 sequestration; high extracellular potassium; membrane potential.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calpain / metabolism*
  • Caspase 1 / metabolism*
  • Female
  • HEK293 Cells
  • Humans
  • Inflammasomes / metabolism*
  • Male
  • Membrane Potentials
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Potassium / metabolism
  • THP-1 Cells

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Calpain
  • Casp1 protein, mouse
  • Caspase 1
  • Potassium
  • Calcium