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Nat Commun. 2018 Dec 5;9(1):5182. doi: 10.1038/s41467-018-07573-4.

NLRP3 lacking the leucine-rich repeat domain can be fully activated via the canonical inflammasome pathway.

Author information

1
Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia. iva.hafner@ki.si.
2
EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, 1000, Ljubljana, Slovenia. iva.hafner@ki.si.
3
Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia.
4
Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital Virgen de la Arrixaca, Carretera Buenavista s/n, 30120 El Palmar, Murcia, Spain.
5
Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia. roman.jerala@ki.si.
6
EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, 1000, Ljubljana, Slovenia. roman.jerala@ki.si.

Abstract

NLRP3 is a cytosolic sensor triggered by different pathogen- and self-derived signals that plays a central role in a variety of pathological conditions, including sterile inflammation. The leucine-rich repeat domain is present in several innate immune receptors, where it is frequently responsible for sensing danger signals and regulation of activation. Here we show by reconstitution of truncated and chimeric variants into Nlrp3-/- macrophages that the leucine-rich repeat domain is dispensable for activation and self-regulation of NLRP3 by several different triggers. The pyrin domain on the other hand is required to maintain NLRP3 in the inactive conformation. A fully responsive minimal NLRP3 truncation variant reconstitutes peritonitis in Nlrp3-/- mice. We demonstrate that in contrast to pathogen-activated NLRC4, the constitutively active NLRP3 molecule cannot engage wild-type NLRP3 molecules in a self-catalytic oligomerization. This lack of signal amplification is likely a protective mechanism to decrease sensitivity to endogenous triggers to impede autoinflammation.

PMID:
30518920
PMCID:
PMC6281599
DOI:
10.1038/s41467-018-07573-4
[Indexed for MEDLINE]
Free PMC Article

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