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

Cell Reports
Yifei ZhangYan Shi

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.

Citations

Dec 24, 2018·Cardiovascular Research·Coert J ZuurbierSean M Davidson
Aug 17, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Paras K MishraTakashi Matsui
Jun 24, 2020·Infection and Immunity·Cecilia CasaravillaÁlvaro Díaz
Jul 30, 2019·Journal of Cardiovascular Pharmacology·Ali RaufSean M Davidson
Nov 15, 2020·Basic Research in Cardiology·Zhenhe HeDerek M Yellon
Apr 15, 2021·Cellular & Molecular Immunology·Seungwha PaikEun-Kyeong Jo
Jul 16, 2021·Journal of Cardiovascular Pharmacology and Therapeutics·Sergey V PopovJames M Downey
Aug 13, 2021·Frontiers in Immunology·Hua Bai, Qifang Zhang
Dec 1, 2021·Essays in Biochemistry·Kishore Aravind Ravichandran, Michael T Heneka

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Methods Mentioned

BETA
fluorescence microscopy
GTPases
transfection
co-immunoprecipitation
GTPase
glucosylation
PMA
flow cytometry
co-IP
PCR

Software Mentioned

Mascot
Pulse
ImageJ
GraphPad Prism
GPSCCD
HEKA Elektronik

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