Ate1‐mediated posttranslational arginylation is essential for stress response regulation and mutagenesis suppression

Arginylation is a posttranslational modification which leads to addition of an extra arginine to an existing peptide chain, thus changing the de facto primary sequence and the surface change. This process is evolutionarily conserved and mainly mediated by arginyltransferase1 (Ate1). While earlier studies found that the overall arginylation activity often increases during stressing conditions including heat shock, oxidative stress, and injury, little is known about the role of arginylation or Ate1 in these conditions. In our study by using multiple types of eukaryotic cells as test models, we found that Ate1/arginylation is essential for stress response, apoptosis and mutagenesis suppression. Knockout of Ate1 in cells leads to a retardation of stress response and the diminish of apoptosis and cell death during exposure of high doses of stressing factors including heat shock, oxidative and osmotic stress, heavy metal and radiation. We demonstrated that Ate1 and its arginylation activity are up‐regulated during stress and activate the intrinsic apoptotic pathway with dependence on the mitochondria‐related apoptosis‐inducing factor (Aif1), but not directly on the ubiquitin‐proteasome system or Caspase (Yca1). Moreover, over‐expression of Ate1 also leads to cell death which depends on its enzymatic activity. Furthermore, we found that Ate1/arginylation is required to suppress mutagenesis in the population during DNA damaging stress. Our data thereby explain the basis for the involvement of arginylation in physiological and diseased conditions by its regulation of cell death and/or mutagenesis. We also uncover a novel mechanism by which a posttranslational modification exerts a global effect on mutagenesis. Support or Funding Information NIH R01GM107333 DoD/CDMRP PC140622 and PC141013 ACS IRG‐98‐277‐13 Sylvester Comprehensive Cancer Center Developmental Grant