Abstract
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 (ate1) 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 in vivo has never been systematically determined. This gap of knowledge leads to difficulties for interpreting the involvements of ATE1 in diseases pathogenesis. Since ate1 is highly conserved between human and the unicellular organism Schizosaccharomyces pombe (S. pombe), we take advantage of the gene-knockout library of S. pombe, to investigate the genetic interactions between ate1 and other genes in a systematic and unbiased manner. By this approach, we found that ate1 has a surprisingly small and focused impact size. Among the 3659 tested genes, which covers nearly 75% of the genome of S. pombe, less than 5% of them displayed significant genetic interactions with ate1. Furthermore, these ate1-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 ate1. Our results suggested that ATE1 specifically regulates a handful of cellular processes in vivo, which will provide critical mechanistic leads for studying the involvements of ATE1 in normal physiologies as well as in diseased conditions.
Highlights
Protein posttranslational modifications (PTM) change protein properties without requiring de novo synthesis
S. pombe usually exists in a haploid form and reproduces by symmetric division, they can be induced to perform mating, during which chromosome recombination proceeds in a relatively high rate
By using the above-mentioned synthetic knockout approach, we examined the effects of combining ate1-knockout with 3721 individual knockouts in a S. pombe library, in which most of these genes were functionally annotated by either experimental evidence or prediction based on known orthologs
Summary
Protein posttranslational modifications (PTM) change protein properties without requiring de novo synthesis. PTMs are frequently relied upon to respond to acute stress or cellular signaling, and are often used to activate lateral response factors such as transcription or epigenetic modulations For these reasons, dysregulation of PTMs are often indicated in cardiovascular diseases where stress response or cellular signaling play critical roles. Inducible systematic deletion of ate appears to cause rapid weight loss, damaged spermatogenesis, neurological perturbations, and early lethality in adult mice (Brower and Varshavsky, 2009). In addition to these involvement in cardiovascular and metabolic abnormalities, a dysregulation of ATE1 is indicated in cancer as well. The physiological role of ATE1 (and its arginylation activity) remains poorly understood, which adds to the difficulty of interpreting its involvements in normal conditions or diseases
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 call
