Nuclear Receptor Coactivator 6 is a Critical Regulator of NLRP3 Inflammasome Activation and Gouty Arthritis

Transcriptional coactivators regulate the rate of gene expression in the nucleus, but their role in the extranuclear sites is largely unknown. Here, we demonstrated that nuclear receptor coactivator 6 (NCOA6) translocated to the cytoplasm, then was incorporated to NLRP3 inflammasome complex, and acquired a new function of “activation of inflammation and innate immune response”, beyond its original function of nuclear coactivation, in monocytes and macrophages. Mechanistically, cytoplasmic NCOA6 directly interacted with NACHT domain of NLRP3 and then promoted NLRP3 activity. Genetic ablation of Ncoa6 substantially attenuated severity of mouse models 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 of gout patients and its signature was significantly enriched in the gout macrophages in transcriptome profiling. Conclusively, NCOA6 is a critical regulator of the NLRP3 inflammasome activation and therefore a promising target for NLRP3-dependent diseases, including gout. Overall design: To systematically understand function of NCOA6 in monocytes/macrophages, we conducted global transcriptome profiling of bone marrow-derived macrophages (BMDMs) isolated from Ncoa6-KO (Ncoa6^(fl/fl)LysM^CRE) mice, whose macrophages specifically do not express Ncoa6, and Wild type (WT, Ncoa6^(fl/fl)) mice, which express Ncoa6, and compared the resulting profiles.