title: MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production.
abstract: Neddylation is a posttranslational protein modification that conjugates ubiquitin-like protein neural precursor cell-expressed developmentally downregulated protein 8 (NEDD8) to target proteins and regulates diverse cellular processes. MLN4924, a novel NEDD8 activating enzyme inhibitor, which has emerged as a promising anticancer drug, has a multifaceted function by inhibiting the process of neddylation. However, the potential roles of MLN4924 and neddylation in IFN-β production remain unknown. In this study, we show that MLN4924 inhibits TLR3/4- and retinoic acid-inducible gene-I-induced IFN-β expression in different cells, whereas NEDD8 knockdown had no effects on IFN-β expression. The ability of the MLN4924 to inhibit IFN-β production was confirmed in vivo, as mice treated with MLN4924 exhibited decreased levels of IFN-β upon LPS or polyinosinic-polycytidylic acid stimulation. Furthermore, we show that MLN4924 inhibits IFN regulatory factor 3 (IRF3) transcriptional activation and prevents IRF3 binding to IFN-β promoter. Our findings suggest that MLN4924 inhibits TLR3/4- and retinoic acid-inducible gene-I-induced IFN-β expression by preventing IRF3 binding to the IFN-β promoter, with a neddylation-independent manner. Therefore, our results provide new insight into the mechanism of MLN4924 and may have significant implications for the treatment of MLN4924.
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Wanwan
authors.initials: W
authors.lastname: Huai
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Zhongxia
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China wzhao@sdu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
mesh_terms: D000818:Animals; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology*; D005260:Female; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000075687:NEDD8 Protein; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects; D014452:Ubiquitins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D003517:Cyclopentanes; D050838:Interferon Regulatory Factor-3; D000075687:NEDD8 Protein; C513172:Nedd8 protein, mouse; D011743:Pyrimidines; D014452:Ubiquitins; D016899:Interferon-beta; C539933:pevonedistat