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首页> 外文期刊>Journal of Molecular Biology >Inhibition of cullin RING ligases by cycle inhibiting factor: evidence for interference with Nedd8-induced conformational control.
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Inhibition of cullin RING ligases by cycle inhibiting factor: evidence for interference with Nedd8-induced conformational control.

机译：循环抑制因子抑制cullin RING连接酶：干扰Nedd8诱导的构象控制的证据。

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摘要

Cycle inhibiting factor (Cif) is produced by pathogenic intracellular bacteria and injected into the host cells via a type III secretion system. Cif is known to interfere with the eukaryotic cell cycle by inhibiting the function of cullin RING E3 ubiquitin ligases (CRLs). Cullin proteins form the scaffold protein of CRLs and are modified with the ubiquitin-like protein Nedd8, which exerts important conformational control required for CRL activity. Cif has recently been shown to catalyze the deamidation of Gln40 in Nedd8 to Glu. Here, we addressed how Nedd8 deamidation inhibits CRL activity. Our results indicate that Burkholderia pseudomallei Cif (also known as CHBP) inhibits the deconjugation of Nedd8 in vivo by inhibiting binding of the deneddylating COP9 signalosome (CSN) complex. We provide evidence that the reduced binding of CSN and the inhibition of CRL activity by Cif are due to interference with Nedd8-induced conformational control, which is dependent on the interaction between the Nedd8 hydrophobic patch and the cullin winged-helix B subdomain. Of note, mutation of Gln40 to Glu in ubiquitin, an additional target of Cif, inhibits the interaction between the hydrophobic surface of ubiquitin and the ubiquitin-binding protein p62/SQSTM1, showing conceptually that Cif activity can impair ubiquitin/ubiquitin-like protein non-covalent interactions. Our results also suggest that Cif may exert additional cellular effects by interfering with the association between ubiquitin and ubiquitin-binding proteins.
机译：循环抑制因子（Cif）由病原性细胞内细菌产生，并通过III型分泌系统注入宿主细胞。已知Cif通过抑制cullin RING E3泛素连接酶（CRL）的功能来干扰真核细胞周期。 Cullin蛋白形成CRL的支架蛋白，并被泛素样蛋白Nedd8修饰，后者发挥CRL活性所需的重要构象控制。最近发现Cif可以催化Nedd8中的Gln40脱酰胺成Glu。在这里，我们解决了Nedd8脱酰胺如何抑制CRL活性。我们的结果表明，伯克霍尔德氏菌假单胞菌Cif（也称为CHBP）通过抑制树突状COP9信号体（CSN）复合物的结合在体内抑制Nedd8的结合。我们提供的证据表明，Cif减少的结合和Cif对CRL活性的抑制是由于干扰Nedd8诱导的构象控制，这取决于Nedd8疏水性斑块与cullin有翼螺旋B子域之间的相互作用。值得注意的是，泛素（Cif的另一个靶标）中的Gln40突变为Glu抑制了泛素的疏水表面与泛素结合蛋白p62 / SQSTM1之间的相互作用，从概念上证明了Cif活性可损害泛素/泛素样蛋白非-共价相互作用。我们的结果还表明，Cif可能通过干扰泛素和泛素结合蛋白之间的结合而发挥其他细胞作用。

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