title: Innate immune and chemically triggered oxidative stress modifies translational fidelity.
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.
authors: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, USA.
authors: Nir
authors: N
authors: Netzer
authors: Jeffrey M
authors: JM
authors: Goodenbour
authors: Alexandre
authors: A
authors: David
authors: Kimberly A
authors: KA
authors: Dittmar
authors: Richard B
authors: RB
authors: Jones
authors: Jeffrey R
authors: JR
authors: Schneider
authors: David
authors: D
authors: Boone
authors: Eva M
authors: EM
authors: Eves
authors: Marsha R
authors: MR
authors: Rosner
authors: James S
authors: JS
authors: Gibbs
authors: Alan
authors: A
authors: Embry
authors: Brian
authors: B
authors: Dolan
authors: Suman
authors: S
authors: Das
authors: Heather D
authors: HD
authors: Hickman
authors: Peter
authors: P
authors: Berglund
authors: Jack R
authors: JR
authors: Bennink
authors: Jonathan W
authors: JW
authors: Yewdell
authors: Tao
authors: T
authors: Pan
mesh_terms: D000256:Adenoviridae / Q000502:physiology; D000818:Animals; D005815:Genetic Code; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D008024:Ligands; D008715:Methionine / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D019255:NADPH Oxidases / Q000378:metabolism; D009975:Orthomyxoviridae / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012358:RNA, Transfer, Met / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013379:Substrate Specificity; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D046249:Transfer RNA Aminoacylation / Q000187:drug effects / Q000502:physiology*
chemical_list: D008024:Ligands; D012358:RNA, Transfer, Met; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors; D008715:Methionine; D019255:NADPH Oxidases