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Failure of RQC machinery causes protein aggregation and proteotoxic stress

机译:RQC机制的故障会导致蛋白质聚集和蛋白毒性应激

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摘要

Translation of messenger RNAs lacking a stop codon results in the addition of a carboxy-terminal poly-lysine tract to the nascent polypeptide, causing ribosome stalling. Non-stop proteins and other stalled nascent chains are recognized by the ribosome quality control (RQC) machinery and targeted for proteasomal degradation. Failure of this process leads to neurodegeneration by unknown mechanisms. Here we show that deletion of the E3 ubiquitin ligase Ltn1p in yeast, a key RQC component, causes stalled proteins to form detergent-resistant aggregates and inclusions. Aggregation is dependent on a C-terminal alanine/threonine tail that is added to stalled polypeptides by the RQC component, Rqc2p. Formation of inclusions additionally requires the poly-lysine tract present in non-stop proteins. The aggregates sequester multiple cytosolic chaperones and thereby interfere with general protein quality control pathways. These findings can explain the proteotoxicity of ribosome-stalled polypeptides and demonstrate the essential role of the RQC in maintaining proteostasis.
机译:缺少终止密码子的信使RNA的翻译导致新生多肽上增加了羧基末端的聚赖氨酸束,导致核糖体失速。核糖体质量控制(RQC)机器识别出不间断的蛋白质和其他停滞的新生链,并靶向进行蛋白酶体降解。该过程的失败导致未知机制引起的神经变性。在这里,我们表明,酵母中E3泛素连接酶Ltn1p的缺失是RQC的关键组成部分,它导致失速的蛋白质形成抗洗涤剂的聚集体和内含物。聚集取决于通过RQC组件Rqc2p添加到停滞多肽中的C末端丙氨酸/苏氨酸尾巴。内含物的形成还需要不间断蛋白质中存在的聚赖氨酸束。聚集体螯合多种胞质伴侣,从而干扰一般的蛋白质质量控​​制途径。这些发现可以解释核糖体陈旧的多肽的蛋白毒性,并证明RQC在维持蛋白稳定中的重要作用。

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  • 来源
    《Nature》 |2016年第7593期|191-195|共5页
  • 作者单位

    Max Planck Inst Biochem, Dept Cellular Biochem, Klopferspitz 18, D-82152 Martinsried, Germany;

    Max Planck Inst Biochem, Dept Cellular Biochem, Klopferspitz 18, D-82152 Martinsried, Germany;

    Max Planck Inst Biochem, Dept Cellular Biochem, Klopferspitz 18, D-82152 Martinsried, Germany;

    Max Planck Inst Biochem, Dept Cellular Biochem, Klopferspitz 18, D-82152 Martinsried, Germany;

    Max Planck Inst Biochem, Dept Cellular Biochem, Klopferspitz 18, D-82152 Martinsried, Germany;

    Max Planck Inst Biochem, Dept Cellular Biochem, Klopferspitz 18, D-82152 Martinsried, Germany;

    Max Planck Inst Biochem, Dept Cellular Biochem, Klopferspitz 18, D-82152 Martinsried, Germany;

  • 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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  • 正文语种 eng
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