MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production

The Journal of Immunology : Official Journal of the American Association of Immunologists
Hui SongWei Zhao

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. Therefor...Continue Reading

References

May 6, 2003·The Journal of Biological Chemistry·Heidi M MendozaRonald T Hay
May 3, 2005·Nature Reviews. Immunology·Leonidas C Platanias
Sep 19, 2006·Immunity·Daniel B Stetson, Ruslan Medzhitov
Jan 6, 2009·Immunological Reviews·Osamu Takeuchi, Shizuo Akira
Apr 11, 2009·Nature·Teresa A SoucySteven P Langston
May 28, 2011·Immunity·Yueh-Ming Loo, Michael Gale
Jan 10, 2012·Nature Reviews. Immunology·José M González-NavajasEyal Raz
Feb 11, 2012·Trends in Immunology·Ben X Wang, Eleanor N Fish
Feb 11, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Wei ZhaoChengjiang Gao
Jul 18, 2012·Expert Opinion on Investigational Drugs·Steffan T NawrockiJennifer S Carew
Jan 10, 2013·PLoS Pathogens·David J StanleyJohn D Gross
May 18, 2013·Nature Reviews. Immunology·Luke A J O'NeillAndrew G Bowie
Sep 18, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lijuan WangChengjiang Gao
Dec 23, 2014·Nature Reviews. Molecular Cell Biology·Radoslav I EnchevMatthias Peter
Apr 1, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Wanwan HuaiWei Zhao
Apr 30, 2015·Cell Reports·Jessica S BrownStephen P Jackson

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Citations

Nov 28, 2017·Cellular & Molecular Immunology·Kun Han, Jiyan Zhang
Aug 5, 2020·Immunity, Inflammation and Disease·Yun Lu, Xuguang Yang
Jul 12, 2019·Frontiers in Immunology·Guangqing YuWuhan Xiao
Oct 8, 2020·The FEBS Journal·Tao Zou, Jiyan Zhang
Dec 30, 2020·Brain : a Journal of Neurology·Kicheol KimSergio E Baranzini

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