Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival
Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival
复制标题
DOI：
10.1016/j.celrep.2020.108599
复制
发表时间：
2021-01-05
期刊：
影响因子：
8.8
通讯作者：
Inada, Toshifumi
中科院分区：
文献类型：
--
作者：
Udagawa, Tsuyoshi;Seki, Moeka;Inada, Toshifumi
核糖体相关质量控制(RQC)可以缓解停滞的核糖体，并消除可能导致神经变性的潜在有毒新生多肽链(NCS)。在RQC过程中，Rqc2用C-末端丙氨酸和苏氨酸(CAT)尾修饰NCS。猫尾酒促进NCS的泛素化以降解蛋白酶体，而萌芽酵母中的RQC故障通过猫尾巴NC聚集破坏蛋白稳定。然而，猫尾巴及其在哺乳动物中的细胞毒性在很大程度上仍未确定。我们证明了NEMF，一个哺乳动物的Rqc2同源物，修改了哺乳动物中主要错误的mRNAs的翻译产物，C-末端的尾巴主要由丙氨酸和其他几个氨基酸组成。过度产生不间断的mRNAs诱导NC聚集和caspase-3依赖的细胞凋亡，并损害神经元的形态发生，而NEMF的耗竭可以改善这一点。此外，我们发现均聚丙氨酸拖尾至少部分解释了猫尾巴的细胞毒性。这些发现解释了猫尾NCS的细胞毒性，并证明了RQC对正常神经元形态发生和细胞存活的生理学意义。
Ribosome-associated quality control (RQC) relieves stalled ribosomes and eliminates potentially toxic nascent polypeptide chains (NCs) that can cause neurodegeneration. During RQC, RQC2 modifies NCs with a C-terminal alanine and threonine (CAT) tail. CAT tailing promotes ubiquitination of NCs for proteasomal degradation, while RQC failure in budding yeast disrupts proteostasis via CAT-tailed NC aggregation. However, the CAT tail and its cytotoxicity in mammals have remained largely uncharacterized. We demonstrate that NEMF, a mammalian RQC2 homolog, modifies translation products of nonstop mRNAs, major erroneous mRNAs in mammals, with a C-terminal tail mainly composed of alanine with several other amino acids. Overproduction of nonstop mRNAs induces NC aggregation and caspase-3-dependent apoptosis and impairs neuronal morphogenesis, which are ameliorated by NEMF depletion. Moreover, we found that homopolymeric alanine tailing at least partially accounts for CAT-tail cytotoxicity. These findings explain the cytotoxicity of CAT-tailed NCs and demonstrate physiological significance of RQC on proper neuronal morphogenesis and cell survival.