Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis
作者机构：Center for Integrative Rheumatoid Transcriptomics and DynamicsThe Catholic University of KoreaSeoul 06591Republic of Korea Department of Biomedicine&Health SciencesThe Catholic University of KoreaSeoul 06591Republic of Korea Department of PharmacologyAsan Medical CenterUniversity of Ulsan College of MedicineSeoul 05505Republic of Korea Bio-Medical Institute of TechnologyUniversity of UlsanSeoul 05505Republic of Korea Department of Microbiology and ImmunologySeoul National University College of MedicineSeoul 03080Republic of Korea Institute of Infectious DiseasesSeoul National University College of MedicineSeoul 03080Republic of Korea Division of RheumatologyDepartment of Internal MedicineThe Catholic University of KoreaSeoul 06591Republic of Korea
出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)
年 卷 期：2024年第21卷第3期
页 面：227-244页
核心收录：
学科分类：100506[医学-中医内科学] 1005[医学-中医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学]
主 题：Nuclear receptor coactivator 6 Nuclear-to-cytoplasmic translocation NLRP3 inflammasome NACHT domain Gouty arthritis
摘 要：Transcriptional coactivators regulate the rate of gene expression in the nucleus.Nuclear receptor coactivator 6(NCOA6),a coactivator,has been implicated in embryonic development,metabolism,and cancer pathogenesis,but its role in innate immunity and inflammatory diseases remains unclear.Here,we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory conditions.Unexpectedly,nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC,forming cytoplasmic specks.Mechanistically,NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3,promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1βand active caspase-1.Of note,Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3^(R258W) gain-of-function mutation in macrophages.Genetic ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases,folic-induced acute tubular necrosis and crystal-induced arthritis,in mice.Consistent with these findings,NCOA6 was highly expressed in macrophages derived from gout patients,and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling results.Conclusively,NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases,including gout.
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