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ERFAD - a novel flavoprotein in endoplasmic reticulum-associated degradation

机译：ERFAD-内质网相关降解中的新型黄素蛋白

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摘要

In eukaryotic cells, the oxidative folding of secreted proteins takes place in the endoplasmic reticulum (ER). Proteins that fail to fold into their native structure are removed from the ER by the ER-associated degradation (ERAD) machinery. In this study, we first identified in a bioinformatics analysis, and subsequently biochemically characterized a novel protein that is involved in this process - the ER-flavoprotein associated with degradation (ERFAD). Human ERFAD is a flavoprotein that interacts with three partners: ERp90, OS-9 and SEL1L. ERp90 is a novel member of the protein disulfide isomerase family while SEL1L and OS-9 are important and well-characterized components of the ERAD machinery. The interaction between ERFADrnand SEL1L as well as ERFAD and OS-9 provided a link to ERAD. Indeed, the degradation of an ERAD-model substrate and the accumulation of polyubiquitinated proteins are significantly delayed when ERFAD is down-regulated by siRNA-mediated knockdown. Below, we show that the novel protein ERFAD functions in a multiprotein complex and that it is involved in ERAD. Finally, using recombinantly expressed purified protein we could show that ERFAD binds FAD that can be reduced by NADPH. We therefore speculate that ERFAD which is unique in the ER in its binding of both FAD and NADPH performs a previously unrecognized redox activity in ERAD.
机译：在真核细胞中，分泌蛋白的氧化折叠发生在内质网（ER）中。不能折叠成其天然结构的蛋白质通过ER相关降解（ERAD）机制从ER中去除。在这项研究中，我们首先在生物信息学分析中进行了鉴定，然后在生物化学上表征了参与此过程的新型蛋白质-与降解相关的ER-黄素蛋白（ERFAD）。人ERFAD是一种黄素蛋白，可与三个伴侣（ERp90，OS-9和SEL1L）相互作用。 ERp90是蛋白质二硫键异构酶家族的新成员，而SEL1L和OS-9是ERAD机械中重要且特征明确的组件。 ERFADrn和SEL1L以及ERFAD和OS-9之间的交互提供了到ERAD的链接。实际上，当ERFAD被siRNA介导的敲低下调时，ERAD模型底物的降解和聚泛素化蛋白质的积累会大大延迟。下面，我们显示了新型蛋白ERFAD在多蛋白复合物中起作用，并且它参与了ERAD。最后，使用重组表达的纯化蛋白，我们可以证明ERFAD结合可被NADPH还原的FAD。因此，我们推测，ERFAD在ER中与FAD和NADPH结合均具有独特性，在ERAD中执行了以前无法识别的氧化还原活性。

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    《Futura》 |2009年第1期|69-72|共4页
  • 作者

    Jan Riemer;

  • 作者单位

    Department of Biology, Institute of Biochemistry, Swiss Federal Institute of Technology Zurich (ETH), Zurich, Switzerland;

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