AUTHOR=Wiley David J. , D’Urso Gennaro , Zhang Fangliang 

TITLE=Posttranslational Arginylation Enzyme Arginyltransferase1 Shows Genetic Interactions With Specific Cellular Pathways in vivo

JOURNAL=Frontiers in Physiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00427

DOI=10.3389/fphys.2020.00427

ISSN=1664-042X

ABSTRACT=<p>Arginyltransferase1 (ATE1) is a conserved enzyme in eukaryotes mediating posttranslational arginylation, the addition of an extra arginine to an existing protein. In mammals, the dysregulations of the ATE1 gene (<italic>ate1</italic>) is shown to be involved in cardiovascular abnormalities, cancer, and aging-related diseases. Although biochemical evidence suggested that arginylation may be involved in stress response and/or protein degradation, the physiological role of ATE1 <italic>in vivo</italic> has never been systematically determined. This gap of knowledge leads to difficulties for interpreting the involvements of ATE1 in diseases pathogenesis. Since <italic>ate1</italic> is highly conserved between human and the unicellular organism <italic>Schizosaccharomyces pombe</italic> (<italic>S. pombe</italic>), we take advantage of the gene-knockout library of <italic>S. pombe</italic>, to investigate the genetic interactions between <italic>ate1</italic> and other genes in a systematic and unbiased manner. By this approach, we found that <italic>ate1</italic> has a surprisingly small and focused impact size. Among the 3659 tested genes, which covers nearly 75% of the genome of <italic>S. pombe</italic>, less than 5% of them displayed significant genetic interactions with <italic>ate1</italic>. Furthermore, these <italic>ate1</italic>-interacting partners can be grouped into a few discrete clustered categories based on their functions or their physical interactions. These categories include translation/transcription regulation, biosynthesis/metabolism of biomolecules (including histidine), cell morphology and cellular dynamics, response to oxidative or metabolic stress, ribosomal structure and function, and mitochondrial function. Unexpectedly, inconsistent to popular belief, very few genes in the global ubiquitination or degradation pathways showed interactions with <italic>ate1</italic>. Our results suggested that ATE1 specifically regulates a handful of cellular processes <italic>in vivo</italic>, which will provide critical mechanistic leads for studying the involvements of ATE1 in normal physiologies as well as in diseased conditions.</p>