Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface

The Journal of Allergy and Clinical Immunology
Fiona MoghaddasSeth L Masters

Abstract

Monogenic autoinflammatory disorders are characterized by dysregulation of the innate immune system, for example by gain-of-function mutations in inflammasome-forming proteins, such as NOD-like receptor family CARD-containing 4 protein (NLRC4). Here we investigate the mechanism by which a novel mutation in the leucine-rich repeat (LRR) domain of NLRC4 (c.G1965C, p.W655C) contributes to autoinflammatory disease. We studied 2 unrelated patients with early-onset macrophage activation syndrome harboring the same de novo mutation in NLRC4. In vitro inflammasome complex formation was quantified by using flow cytometric analysis of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 techniques and lentiviral transduction were used to generate THP-1 cells with either wild-type or mutant NLRC4 cDNA. Cell death and release of IL-1β/IL-18 were quantified by using flow cytometry and ELISA, respectively. The p.W655C NLRC4 mutation caused increased ASC speck formation, caspase-1-dependent cell death, and IL-1β/IL-18 production. ASC contributed to p.W655C NLRC4-mediated cytokine release but not cell death. Mutation of p.W655 activ...Continue Reading

Citations

May 31, 2018·Current Rheumatology Reports·Cassandra R HarapasSeth L Masters
Feb 16, 2019·Expert Opinion on Biological Therapy·Jorien van der SchaftMarjolein S de Bruin-Weller
Dec 12, 2018·Protein and Peptide Letters·Norio MatsushimaRobert H Kretsinger
Jul 2, 2019·Internal Medicine Journal·Fiona Moghaddas
Jun 13, 2020·Journal of Leukocyte Biology·Warrison A Andrade, Dario S Zamboni
Nov 27, 2019·Rheumatology·Mark KacarSinisa Savic
Jul 8, 2020·International Journal of Molecular Sciences·Jae-Min YukEun-Kyeong Jo
Nov 27, 2019·World Journal of Stem Cells·Maria Teresa ValentiDonato Zipeto
Sep 14, 2019·Nature Reviews. Rheumatology·Charles Anthony Dinarello
Sep 7, 2018·Clinical Science·Fiona Moghaddas, Seth L Masters
Jun 17, 2020·Allergy & Rhinology·Jack JeskeyRobert Hostoffer
Oct 16, 2018·Frontiers in Immunology·Julie BarsalouFabien Touzot
Mar 14, 2019·Journal of Clinical Immunology·Tania SiahanidouMaria Kanariou
Jan 27, 2021·International Journal of Molecular Sciences·Balamurugan Sundaram, Thirumala-Devi Kanneganti
Feb 27, 2021·Frontiers in Cell and Developmental Biology·Man WangYuan Zhang
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Diego Angosto-BazarraPablo Pelegrín
May 27, 2021·Nature Reviews. Rheumatology·Ivona Aksentijevich, Oskar Schnappauf
Nov 17, 2021·Journal of Clinical Immunology·Annemarie SteinerSeth L Masters

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Methods Mentioned

BETA
PCR
ELISA
electrophoresis
flow cytometry
flow
transfection
biopsy

Software Mentioned

PyMOL Molecular Graphics System
PolyPhen
Haplotype Caller
Prism
SIFT
Genome Analysis Toolkit

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