Abstract
Arginyltransferase 1 (Ate1) mediates protein arginylation, a poorly understood protein posttranslational modification (PTM) in eukaryotic cells. Previous evidence suggest a potential involvement of arginylation in stress response and this PTM was traditionally considered anti-apoptotic based on the studies of individual substrates. However, here we found that arginylation promotes cell death and/or growth arrest, depending on the nature and intensity of the stressing factor. Specifically, in yeast, mouse and human cells, deletion or downregulation of the ATE1 gene disrupts typical stress responses by bypassing growth arrest and suppressing cell death events in the presence of disease-related stressing factors, including oxidative, heat, and osmotic stresses, as well as the exposure to heavy metals or radiation. Conversely, in wild-type cells responding to stress, there is an increase of cellular Ate1 protein level and arginylation activity. Furthermore, the increase of Ate1 protein directly promotes cell death in a manner dependent on its arginylation activity. Finally, we found Ate1 to be required to suppress mutation frequency in yeast and mammalian cells during DNA-damaging conditions such as ultraviolet irradiation. Our study clarifies the role of Ate1/arginylation in stress response and provides a new mechanism to explain the link between Ate1 and a variety of diseases including cancer. This is also the first example that the modulation of the global level of a PTM is capable of affecting DNA mutagenesis.
Highlights
As a common response to changing environmental cues, posttranslational modifications (PTMs) of proteins can promptly modulate cellular functions without de novo translation or transcription
When we deleted the evolutionarily conserved ATE1 gene in the budding yeast, S. cerevisiae, we found no obvious effect on growth in non-stressing conditions in nutrient-rich medium (Figures 1a and b)
Using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to probe apoptosis, a programmed cell death event, we found that the deletion of ATE1 greatly attenuated H2O2-induced apoptosis (Figure 2b), which contradicts the prevailing hypothesis for the anti-apoptotic roles for Ate[1] and arginylation.[23,28,29]
Summary
As a common response to changing environmental cues, posttranslational modifications (PTMs) of proteins can promptly modulate cellular functions without de novo translation or transcription. According to the N-end rule, a protein degradation theory that correlates the metabolic stabilities of a peptide to the identity of its N-terminal residue, arginylation constitutes an acute degradation signal conferring a half-life of o3 min.[22] For this reason, previous studies mainly focused on identifying novel substrates for cues of mechanistic insights of arginylation, under the assumption that this modification should lead to a quick degradation On this basis, several studies suggested that a normal activity of arginylation is required for anti-apoptotic activities through proteins such as drosophila inhibitor of apoptosis protein, and degradation of pro-apoptotic fragments of RIPK1 (receptorinteracting serine/threonine protein kinase 1) and BRCA1 (breast cancer 1, early onset) created by the action of caspase or calpain.[23,24,25,26,27] Ate1-mediated arginylation has been traditionally considered to have an anti-apoptotic effect in vivo.[23,27,28,29] arginylation affects a broad range of proteins with diverse functions, some of which are arguably anti-apoptotic.[30] Further complicating the matter, arginylation may regulate protein structure and function independently of protein half-life.[31,32,33,34,35] it may be ineffective or inaccurate to ascribe a global function to Ate[1] based on the identities of a few individual substrates. Our finding is the first example of a PTM having a global effect on DNA mutagenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
