Failure of RQC machinery causes protein aggregation and proteotoxic stress
Failure of RQC machinery causes protein aggregation and proteotoxic stress
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DOI：
10.1038/nature16973
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发表时间：
2016-03-10
期刊：
影响因子：
64.8
通讯作者：
Hartl, F. Ulrich
中科院分区：
文献类型：
--
作者：
Choe, Young-Jun;Park, Sae-Hun;Hartl, F. Ulrich
缺少终止密码子的信使RNA的翻译导致在新生多肽中添加羧基末端多聚赖氨酸段，引起核糖体停滞。不停止蛋白质和其他停滞的新生链被核糖体质量控制（RQC）机制识别，并被蛋白酶体降解为目标。这一过程的失败会导致未知机制的神经退行性变。在这里，我们表明，删除E3泛素连接酶Ltn 1 p在酵母中，一个关键的RQC组件，导致停滞的蛋白质形成耐洗涤剂的聚集体和夹杂物。聚集依赖于通过RQC组分Rqc 2 p添加到停滞多肽的C-末端丙氨酸/苏氨酸尾。内含物的形成还需要存在于非终止蛋白质中的多聚赖氨酸束。聚集体隔离多种胞质伴侣，从而干扰一般蛋白质质量控制途径。这些发现可以解释核糖体停滞多肽的蛋白毒性，并证明RQC在维持蛋白质稳态中的重要作用。
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.