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Direct activation of protein kinases by unanchored polyubiquitin chains

机译：未锚定的多泛素链直接激活蛋白激酶

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摘要

TRAF6 is a ubiquitin ligase that is essential for the activation of NF-kB and MAP kinases in several signalling pathways, including those emanating from the interleukin 1 and Toll-like receptors. TRAF6 functions together with a ubiquitin-conjugating enzyme complex consisting of UBC13 (also known as UBE2N) and UEV1A (UBE2V1) to catalyse Lys63-linked polyubiquitination, which activates the TAK1 (also known as MAP3K7) kinase complex45. TAK1 in turn phosphorylates and activates IkB kinase (IKK), leading to the activation of NF-kB. Although several proteins are known to be polyubiquitinated in the IL1R and Toll-like receptor pathways, it is not clear whether ubiquitination of any of these proteins is important for TAK1 or IKK activation. By reconstituting TAK1 activation in vitro using purified proteins, here we show that free Lys63 polyubiquitin chains, which are not conjugated to any target protein, directly activate TAK1 by binding to the ubiquitin receptor TAB2 (also known as MAP3K7IP2). This binding leads to autophosphorylation and activation of TAK1. Furthermore, we found that unanchored polyubiquitin chains synthesized by TRAF6 and UBCH5C (also known as UBE2D3) activate the IKK complex. Disassembly of the polyubiquitin chains by deubiquitination enzymes prevented TAK1 and IKK activation. These results indicate that unanchored polyubiquitin chains directly activate TAK1 and IKK, suggesting a new mechanism of protein kinase regulation.
机译：TRAF6是一种遍在蛋白连接酶，对于激活多种信号通路（包括白介素1和Toll样受体产生的信号通路）中的NF-kB和MAP激酶至关重要。 TRAF6与由UBC13（也称为UBE2N）和UEV1A（UBE2V1）组成的泛素结合酶复合物共同起作用，以催化Lys63连接的多泛素化作用，从而激活TAK1（也称为MAP3K7）激酶复合物45。 TAK1继而磷酸化并激活IkB激酶（IKK），从而导致NF-kB的激活。尽管已知几种蛋白质在IL1R和Toll样受体途径中被多泛素化，但是尚不清楚这些蛋白质中的任何一种的泛素化对TAK1或IKK激活是否重要。通过使用纯化的蛋白在体外重建TAK1激活，我们显示未与任何靶蛋白未结合的自由Lys63多聚泛素链通过结合至泛素受体TAB2（也称为MAP3K7IP2）直接激活TAK1。这种结合导致TAK1的自磷酸化和激活。此外，我们发现TRAF6和UBCH5C（也称为UBE2D3）合成的未锚定的多聚泛素链激活了IKK复合物。通过去泛素化酶分解多聚泛素链可防止TAK1和IKK活化。这些结果表明未锚定的多聚泛素链直接激活TAK1和IKK，表明蛋白激酶调节的新机制。

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  • 来源
    《Nature》 |2009年第7260期|114-119|共6页
  • 作者

    Zong-Ping Xia; Lijun Sun; Xiang Chen; Gabriel Pineda; Xiaomo Jiang; Anirban Adhikari; Wenwen Zeng; Zhijian J.Chen;

  • 作者单位

    Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA;

    Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA Howard Hughes Medical Institute, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA;

    Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA Howard Hughes Medical Institute, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA;

    Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA;

    Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA;

    Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA;

    Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA;

    Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA Howard Hughes Medical Institute, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148, USA;

  • 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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