Innate immune and chemically triggered oxidative stress modifies translational fidelity.

TitleInnate immune and chemically triggered oxidative stress modifies translational fidelity.
Publication TypeJournal Article
Year of Publication2009
AuthorsNetzer N, Goodenbour JM, David A, Dittmar KA, Jones RB, Schneider JR, Boone D, Eves EM, Rosner MR, Gibbs JS, Embry A, Dolan BP, Das S, Hickman HD, Berglund P, Bennink JR, Yewdell JW, Pan T
JournalNature
Volume462
Issue7272
Pagination522-6
Date Published2009 Nov 26
ISSN1476-4687
KeywordsAdenoviridae, Animals, Genetic Code, Hela Cells, Humans, Immunity, Innate, Ligands, Methionine, Mice, Models, Genetic, NADPH Oxidase, Orthomyxoviridae, Oxidative Stress, Reactive Oxygen Species, RNA, Transfer, Met, Substrate Specificity, Toll-Like Receptors, Transfer RNA Aminoacylation
Abstract

Translational fidelity, essential for protein and cell function, requires accurate transfer RNA (tRNA) aminoacylation. Purified aminoacyl-tRNA synthetases exhibit a fidelity of one 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 tenfold 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.

DOI10.1038/nature08576
Alternate JournalNature