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dc.contributor.authorMoghaddas, F
dc.contributor.authorZeng, P
dc.contributor.authorZhang, Y
dc.contributor.authorSchuetzle, H
dc.contributor.authorBrenner, S
dc.contributor.authorHofmann, SR
dc.contributor.authorBerner, R
dc.contributor.authorZhao, Y
dc.contributor.authorLu, B
dc.contributor.authorChen, X
dc.contributor.authorZhang, L
dc.contributor.authorCheng, S
dc.contributor.authorWinkler, S
dc.contributor.authorLehmberg, K
dc.contributor.authorCanna, SW
dc.contributor.authorCzabotar, PE
dc.contributor.authorWicks, IP
dc.contributor.authorDe Nardo, D
dc.contributor.authorHedrich, CM
dc.contributor.authorZeng, H
dc.contributor.authorMasters, SL
dc.date.accessioned2020-12-17T04:32:07Z
dc.date.available2020-12-17T04:32:07Z
dc.date.issued2018-12-01
dc.identifierpii: S0091-6749(18)30710-3
dc.identifier.citationMoghaddas, F., Zeng, P., Zhang, Y., Schuetzle, H., Brenner, S., Hofmann, S. R., Berner, R., Zhao, Y., Lu, B., Chen, X., Zhang, L., Cheng, S., Winkler, S., Lehmberg, K., Canna, S. W., Czabotar, P. E., Wicks, I. P., De Nardo, D., Hedrich, C. M. ,... Masters, S. L. (2018). Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 142 (6), pp.1956-+. https://doi.org/10.1016/j.jaci.2018.04.033.
dc.identifier.issn0091-6749
dc.identifier.urihttp://hdl.handle.net/11343/255350
dc.description.abstractBACKGROUND: 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.
dc.languageEnglish
dc.publisherMOSBY-ELSEVIER
dc.titleAutoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface
dc.typeJournal Article
dc.identifier.doi10.1016/j.jaci.2018.04.033
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentMedicine and Radiology
melbourne.source.titleJournal of Allergy and Clinical Immunology
melbourne.source.volume142
melbourne.source.issue6
melbourne.source.pages1956-+
dc.rights.licenseCC BY
melbourne.elementsid1336383
melbourne.contributor.authorMasters, Seth
melbourne.contributor.authorMoghaddas, Fiona Eyesun
melbourne.contributor.authorCzabotar, Peter
melbourne.contributor.authorWicks, Ian
melbourne.contributor.authorde Nardo, Dominic
dc.identifier.eissn1097-6825
melbourne.accessrightsOpen Access


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