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首页> 外文期刊>Nature >Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1
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Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1

机译：衣康酸酯是一种抗炎代谢产物，可通过KEAP1的烷基化激活Nrf2。

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摘要

The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood(1-3). Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.
机译：衣康酸内源性代谢物最近已成为巨噬细胞功能的调节剂，但其确切的作用机理仍知之甚少（1-3）。在这里，我们显示衣康酸酯是小鼠和人类巨噬细胞中脂多糖激活抗炎转录因子Nrf2（也称为NFE2L2）所必需的。我们发现衣康酸酯通过半胱氨酸残基的烷基化直接修饰蛋白质。衣康酸酯烷基化蛋白KEAP1上的半胱氨酸残基151、257、288、273和297，使Nrf2能够增加具有抗氧化和抗炎能力的下游基因的表达。 Nrf2的激活是衣康酸酯抗炎作用所必需的。我们描述了一种新的细胞可渗透的衣康酸酯衍生物，4-辛基衣康酸酯的使用，该衍生物可保护体内脂多糖诱导的致死性并减少细胞因子的产生。我们显示，I型干扰素可增强Irg1（也称为Acod1）的表达和衣康酸酯的生产。此外，我们发现衣康酸酯的生产限制了I型干扰素的反应，表明涉及干扰素和衣康酸酯的负反馈回路。我们的发现表明衣康酸酯是一种重要的抗炎代谢产物，它通过Nrf2来限制炎症和调节I型干扰素。

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  • 来源
    《Nature》 |2018年第7699期|113-117|共5页
  • 作者

    Mills Evanna L.; Ryan Dylan G.; Prag Hiran A.; Dikovskaya Dina; Menon Deepthi; Zaslona Zbigniew; Jedrychowski Mark P.; Costa Ana S. H.; Higgins Maureen; Hams Emily; Szpyt John; Runtsch Marah C.; King Martin S.; McGouran Joanna F.; Fischer Roman; Kessler Benedikt M.; McGettrick Anne F.; Hughes Mark M.; Carroll Richard G.; Booty Lee M.; Knatko Elena V.; Meakin Paul J.; Ashford Michael L. J.; Modis Louise K.; Brunori Gino; Sevin Daniel C.; Fallon Padraic G.; Caldwell Stuart T.; Kunji Edmund R. S.; Chouchani Edward T.; Frezza Christian; Dinkova-Kostova Albena T.; Hartley Richard C.; Murphy Michael P.; ONeill Luke A.;

  • 作者单位

    Trinity Coll Dublin, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin, Ireland;

    Trinity Coll Dublin, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin, Ireland;

    Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge CB2 0XY, England;

    Univ Dundee, Jacqui Wood Canc Ctr, Sch Med, Div Canc Res, Dundee DD1 9SY, Scotland;

    Trinity Coll Dublin, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin, Ireland;

    Trinity Coll Dublin, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin, Ireland;

    Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA;

    Univ Cambridge, Hutchison MRC Res Ctr, MRC Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England;

    Univ Dundee, Jacqui Wood Canc Ctr, Sch Med, Div Canc Res, Dundee DD1 9SY, Scotland;

    Trinity Coll Dublin, Sch Med, Trinity Biomed Sci Inst, Dublin, Ireland;

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Trinity Coll Dublin, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin, Ireland;

    Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge CB2 0XY, England;

    Trinity Coll Dublin, Sch Chem, Trinity Biomed Sci Inst, Dublin, Ireland;

    Univ Oxford, Target Discovery Inst, Nuffield Dept Med, Oxford OX3 7FZ, England;

    Univ Oxford, Target Discovery Inst, Nuffield Dept Med, Oxford OX3 7FZ, England;

    Trinity Coll Dublin, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin, Ireland;

    Trinity Coll Dublin, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin, Ireland;

    Trinity Coll Dublin, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin, Ireland;

    GlaxoSmithKline, Gunnelswood Rd, Stevenage, Herts, England;

    Univ Dundee, Jacqui Wood Canc Ctr, Sch Med, Div Canc Res, Dundee DD1 9SY, Scotland;

    Univ Dundee, Sch Med, Div Mol & Clin Med, Dundee DD1 9SY, Scotland;

    Univ Dundee, Sch Med, Div Mol & Clin Med, Dundee DD1 9SY, Scotland;

    GlaxoSmithKline, Gunnelswood Rd, Stevenage, Herts, England;

    GlaxoSmithKline, Pk Rd, Ware, Herts, England;

    GlaxoSmithKline R&D, Cellzome, Heidelberg, Germany;

    Trinity Coll Dublin, Sch Med, Trinity Biomed Sci Inst, Dublin, Ireland;

    Univ Glasgow, WestCHEM Sch Chem, Glasgow G12 8QQ, Lanark, Scotland;

    Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge CB2 0XY, England;

    Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA;

    Univ Cambridge, Hutchison MRC Res Ctr, MRC Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England;

    Univ Dundee, Jacqui Wood Canc Ctr, Sch Med, Div Canc Res, Dundee DD1 9SY, Scotland;

    Univ Glasgow, WestCHEM Sch Chem, Glasgow G12 8QQ, Lanark, Scotland;

    Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge CB2 0XY, England;

    Trinity Coll Dublin, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin, Ireland;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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