Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface
Standard
Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface. / Moghaddas, Fiona; Zeng, Ping; Zhang, Yuxia; Schützle, Heike; Brenner, Sebastian; Hofmann, Sigrun R; Berner, Reinhard; Zhao, Yuanbo; Lu, Bingtai; Chen, Xiaoyun; Zhang, Li; Cheng, Suyun; Winkler, Stefan; Lehmberg, Kai; Canna, Scott W; Czabotar, Peter E; Wicks, Ian P; De Nardo, Dominic; Hedrich, Christian M; Zeng, Huasong; Masters, Seth L.
in: J ALLERGY CLIN IMMUN, Jahrgang 142, Nr. 6, 12.2018, S. 1956-1967.e6.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface
AU - Moghaddas, Fiona
AU - Zeng, Ping
AU - Zhang, Yuxia
AU - Schützle, Heike
AU - Brenner, Sebastian
AU - Hofmann, Sigrun R
AU - Berner, Reinhard
AU - Zhao, Yuanbo
AU - Lu, Bingtai
AU - Chen, Xiaoyun
AU - Zhang, Li
AU - Cheng, Suyun
AU - Winkler, Stefan
AU - Lehmberg, Kai
AU - Canna, Scott W
AU - Czabotar, Peter E
AU - Wicks, Ian P
AU - De Nardo, Dominic
AU - Hedrich, Christian M
AU - Zeng, Huasong
AU - Masters, Seth L
N1 - Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2018/12
Y1 - 2018/12
N2 - BACKGROUND: 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).OBJECTIVE: 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.METHODS: 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.RESULTS: 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 activated the NLRC4 inflammasome complex by engaging with 2 interfaces on the opposing LRR domain of the oligomer. One key set of residues (p.D1010, p.D1011, p.L1012, and p.I1015) participated in LRR-LRR oligomerization when triggered by mutant NLRC4 or type 3 secretion system effector (PrgI) stimulation of the NLRC4 inflammasome complex.CONCLUSION: This is the first report of a mutation in the LRR domain of NLRC4 causing autoinflammatory disease. c.G1965C/p.W655C NLRC4 increased inflammasome activation in vitro. Data generated from various NLRC4 mutations provides evidence that the LRR-LRR interface has an important and previously unrecognized role in oligomerization of the NLRC4 inflammasome complex.
AB - BACKGROUND: 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).OBJECTIVE: 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.METHODS: 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.RESULTS: 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 activated the NLRC4 inflammasome complex by engaging with 2 interfaces on the opposing LRR domain of the oligomer. One key set of residues (p.D1010, p.D1011, p.L1012, and p.I1015) participated in LRR-LRR oligomerization when triggered by mutant NLRC4 or type 3 secretion system effector (PrgI) stimulation of the NLRC4 inflammasome complex.CONCLUSION: This is the first report of a mutation in the LRR domain of NLRC4 causing autoinflammatory disease. c.G1965C/p.W655C NLRC4 increased inflammasome activation in vitro. Data generated from various NLRC4 mutations provides evidence that the LRR-LRR interface has an important and previously unrecognized role in oligomerization of the NLRC4 inflammasome complex.
KW - Journal Article
U2 - 10.1016/j.jaci.2018.04.033
DO - 10.1016/j.jaci.2018.04.033
M3 - SCORING: Journal article
C2 - 29778503
VL - 142
SP - 1956-1967.e6
JO - J ALLERGY CLIN IMMUN
JF - J ALLERGY CLIN IMMUN
SN - 0091-6749
IS - 6
ER -
