ArticleThe Journal of allergy and clinical immunology2018
Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface.
Article in The Journal of allergy and clinical immunology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed, 70 citations in OpenAlex.
- Importance of the inflammasome in gut-brain axis: from pathological driver to therapeutic target.Inflammopharmacology · 2026Review
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- Recent variant discoveries and emerging genetic mechanisms in autoinflammatory diseases.Frontiers in immunology · 2026Review
- An animal model of NLRC4-associated autoinflammation and infantile enterocolitis reveals novel therapeutic strategies.Cellular & molecular immunology · 2025Article
- Somatic Mosaic NLRC4 Variants in Autoinflammatory Diseases: Functional Characterization and Correlation of Mosaicism Levels with Disease Age of Onset and Severity.Journal of clinical immunology · 2025Article
- Challenges in the Diagnosis of Infantile Enterocolitis and Rare Auto-Inflammatory Syndromes: A Case Report and Literature Review.Clinical case reports · 2025Article
- Inflammasome protein scaffolds the DNA damage complex during tumor development.Nature immunology · 2024Article
- An improved understanding of pediatric chronic nonbacterial osteomyelitis pathophysiology informs current and future treatment.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2024Review
- Three cases of autoinflammatory disease with novel NLRC4 mutations, and the first mutation reported in the CARD domain of NLRC4 associated with autoinflammatory infantile enterocolitis (AIFEC).Pediatric rheumatology online journal · 2024Article
- NLRC4, inflammation and colorectal cancer (Review).International journal of oncology · 2024Review
- The NLR family of innate immune and cell death sensors.Immunity · 2024Review
- The role of inflammasomes in human diseases and their potential as therapeutic targets.Signal transduction and targeted therapy · 2024Review
- The 4Pediatric rheumatology online journal · 2024Article
- Cellular models in autoinflammatory disease research.Clinical & translational immunology · 2024Review
- Does Pyroptosis Play a Role in Inflammasome-Related Disorders?International journal of molecular sciences · 2022Review
- Structural mechanisms of inflammasome regulation revealed by cryo-EM studies.Current opinion in structural biology · 2022Review
- Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing.Scientific reports · 2022Article
- Physiological and pathophysiological functions of NLRP6: pro- and anti-inflammatory roles.Communications biology · 2022Review
- Immune-mediated inflammatory diseases with chronic excess of serum interleukin-18.Frontiers in immunology · 2022Review
- NLRC4 GOF Mutations, a Challenging Diagnosis from Neonatal Age to Adulthood.Journal of clinical medicine · 2021Article
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Authors and funding
21 authors at 10 institutions in 5 countries.
Funding
Abstract
backgroundMonogenic 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).
objectiveHere 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.
methodsWe 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.
resultsThe 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.
conclusionThis 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.
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