Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis  

作　　者：Kang-Gu Lee Bong-Ki Hong Saseong Lee Naeun Lee Seung-Whan Kim Donghyun Kim Wan-Uk Kim 

机构地区：[1]Center for Integrative Rheumatoid Transcriptomics and Dynamics,The Catholic University of Korea,Seoul 06591,Republic of Korea [2]Department of Biomedicine&Health Sciences,The Catholic University of Korea,Seoul 06591,Republic of Korea [3]Department of Pharmacology,Asan Medical Center,University of Ulsan College of Medicine,Seoul 05505,Republic of Korea [4]Bio-Medical Institute of Technology,University of Ulsan,Seoul 05505,Republic of Korea [5]Department of Microbiology and Immunology,Seoul National University College of Medicine,Seoul 03080,Republic of Korea [6]Institute of Infectious Diseases,Seoul National University College of Medicine,Seoul 03080,Republic of Korea [7]Division of Rheumatology,Department of Internal Medicine,The Catholic University of Korea,Seoul 06591,Republic of Korea

出　　处：《Cellular & Molecular Immunology》2024年第3期227-244,共18页中国免疫学杂志（英文版）

基　　金：supported by grants from the National Research Foundation of Korea(NRF)funded by the Ministry of Science and ICT(2015R1A3A2032927 and 2021R1A2C1008130).

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.

关 键 词：Nuclear receptor coactivator 6 Nuclear-to-cytoplasmic translocation NLRP3 inflammasome NACHT domain Gouty arthritis 

分 类 号：R259.8[医药卫生—中西医结合]