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

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.

Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1

“…Recently, we began exploring the genetic interactions between ATE1 and thousands of other genes in the fission yeast model system ( Schizosaccharomyces pombe ) (Wiley et al, 2020 ). In this study, we observed that ATE1 interacts with only 5% of other yeast genes in a screening library covering 75% of the predicted open reading frames (ORF).…”

Liquiritin Attenuates Angiotensin II-Induced Cardiomyocyte Hypertrophy via ATE1/TAK1-JNK1/2 Pathway

“…Mitochondria are the main source of oxidative stressors in cells, and studies have shown that the expression of ATE1 increases in proportion to the degree of various stresses [ 39 ]. A large number of genes (at least 19) related to mitochondria or energy production, such as Oma1 and COQ7, were found to have genetic interactions with ATE1 through GO term studies, and those partial proteins have been reported to be involved in the regulation of cardiac hypertrophy [ 56 – 58 ]. Future studies would be required to study which proteins/factors are involved in LIQ downregulating ATE1 expression and its relationship with anticardiac hypertrophy from the stress response.…”

Ablation of arginyl‐tRNA‐protein transferase in oligodendrocytes impairs central nervous system myelination

“…This reduction was presumably due, in part, to cycle progression (Stendel et al, 2007). A subset of genes in the Rho GTPase family (Rho A, B, C) were shown to interact with Ate1, using a systematic approach (Willey et al, 2020). These studies suggest that Ate1 is associated with cytoskeletal signaling pathways during OL development, and that changes in their regulators can lead to pathological states.…”