title: Selective inhibition of the NLRP3 inflammasome by targeting to promyelocytic leukemia protein in mouse and human.
abstract: The functional activities of the tumor suppressor promyelocytic leukemia protein (PML) are mostly associated with its nuclear location. In the present study, we discovered an unexpected role of PML in NLRP3 inflammasome activation. In PML-deficient macrophages, the production of IL-1β was strongly impaired. The expression of pro-IL-1β, NLRP3, ASC, and procaspase-1 was not affected in Pml(-/-) macrophages. PML deficiency selectively reduced the processing of procaspase-1. We further showed that PML is required for the assembly of the NLRP3 inflammasome in reconstitution experiment. All PML isoforms were capable of stimulating NLRP3 inflammasome activation. In Pml(-/-) macrophages, the generation of reactive oxygen species and release of mitochondrial DNA were decreased. The involvement of PML in inflammasome activation constitutes an important activity of PML and reveals a new mechanism underlying the inflammasome activation. In addition, downregulation of PML by arsenic trioxide suppressed monosodium urate (MSU)-induced IL-1β production, suggesting that targeting to PML could be used to treat NLRP3 inflammasome-associated diseases.
authors: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
authors: Yu-Hsun
authors: YH
authors: Lo
authors: Yu-Wen
authors: YW
authors: Huang
authors: Yung-Hsuan
authors: YH
authors: Wu
authors: Chi-Shan
authors: CS
authors: Tsai
authors: Yu-Chuan
authors: YC
authors: Lin
authors: Shu-Ting
authors: ST
authors: Mo
authors: Wen-Chih
authors: WC
authors: Kuo
authors: Ya-Ting
authors: YT
authors: Chuang
authors: Si-Tse
authors: ST
authors: Jiang
authors: Hsiu-Ming
authors: HM
authors: Shih
authors: Ming-Zong
authors: MZ
authors: Lai
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D020170:Caspase 1 / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects; D017353:Gene Deletion; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D010087:Oxides / Q000494:pharmacology; D000071156:Promyelocytic Leukemia Protein; D017382:Reactive Oxygen Species / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D001152:Arsenicals; D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D006131:Growth Inhibitors; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; D010087:Oxides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D020170:Caspase 1; D000077237:Arsenic Trioxide