Innate immune and chemically triggered oxidative stress modifies translational fidelity.
Innate immune and chemically triggered oxidative stress modifies translational fidelity.
复制标题
作者：
翻译保真度对于蛋白质和细胞功能至关重要，需要准确的 tRNA 氨酰化。纯化的氨酰基-tRNA 合成酶的保真度为每 10,000 至 100,000 次偶联 1 个错误。然而，体内 tRNA 氨酰化的准确性尚不确定，并且可能要低得多。在这里，我们发现在哺乳动物细胞中，蛋白质合成中使用的大约 1% 的蛋氨酸 (Met) 残基被氨酰化为非蛋氨酰 tRNA。值得注意的是，当细胞暴露于活的或非传染性的病毒、Toll 样受体配体或化学诱导的氧化应激时，Met 丙酰基化会增加高达 10 倍。 Met 被异酰基化为特定的非甲硫氨酰 tRNA 家族，这些 Met 异酰基化 tRNA 用于翻译。 Met-丙酰基化被细胞氧化酶抑制剂阻断，表明活性氧 (ROS) 是丙酰基化的触发因素。在测试的六种氨基酸中，tRNA 错误酰化仅发生在 Met 中。由于已知 Met 残基可以保护蛋白质免受 ROS 介导的损伤，因此我们提出 Met 酰基化功能适应性地增加 Met 掺入蛋白质中，以保护细胞免受氧化应激。在展示解码 mRNA 的意想不到的条件方面时，我们的研究结果说明了考虑遗传密码的替代迭代的重要性。
Translational fidelity, essential for protein and cell function, requires accurate tRNA aminoacylation. Purified aminoacyl-tRNA synthetases exhibit a fidelity of 1 error per 10,000 to 100,000 couplings. The accuracy of tRNA aminoacylation in vivo is uncertain, however, and might be considerably lower. Here, we show that in mammalian cells, approximately 1% of methionine (Met) residues used in protein synthesis are aminoacylated to non-methionyl-tRNAs. Remarkably, Met-misacylation increases up to 10-fold upon exposing cells to live or non-infectious viruses, toll-like receptor ligands, or chemically induced oxidative stress. Met is misacylated to specific non-methionyl-tRNA families, and these Met-misacylated tRNAs are used in translation. Met-misacylation is blocked by an inhibitor of cellular oxidases, implicating reactive oxygen species (ROS) as the misacylation trigger. Among six amino acids tested, tRNA misacylation occurs exclusively with Met. As Met residues are known to protect proteins against ROS-mediated damage, we propose that Met-misacylation functions adaptively to increase Met incorporation into proteins to protect cells against oxidative stress. In demonstrating an unexpected conditional aspect of decoding mRNA, our findings illustrate the importance of considering alternative iterations of the genetic code.
登录
查看更多内容
DOI：
10.1073/pnas.0802779105
发表时间：
2008-10-28
影响因子：
11.1
作者：
Bender, Aline;Hajieva, Parvana;Moosmann, Bernd
通讯作者：
Moosmann, Bernd
DOI：
10.1073/pnas.0809179105
发表时间：
2008-10-28
影响因子：
11.1
作者：
Ruan, Benfang;Palioura, Sotiria;Soell, Dieter
通讯作者：
Soell, Dieter
影响因子：
11.4
作者：
Silva, Raquel M.;Paredes, Joao A.;Santos, Manuel As
通讯作者：
Santos, Manuel As
DOI：
10.1073/pnas.2136934100
发表时间：
2003-12-23
影响因子：
11.1
作者：
Ahel, I;Korencic, D;Söll, D
通讯作者：
Söll, D
DOI：
10.1073/pnas.0809677105
发表时间：
2008-11-25
影响因子：
11.1
作者：
Malhotra, Jyoti D.;Miao, Hongzhi;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.