Protein arginylation regulates cellular stress response by stabilizing HSP70 and HSP40 transcripts

Abstract

ATE1-mediated post-translational addition of arginine to a protein has been shown to regulate activity, interaction, and stability of the protein substrates. Arginylation has been linked to many different stress conditions, namely ER stress, cytosolic misfolded protein stress, and nitrosative stress. However, clear understanding about the effect of arginylation in cellular stress responses is yet to emerge. In this study, we investigated the role of arginylation in heat-stress response. Our findings suggest that Ate1 knock out (KO) cells are more susceptible to heat stress compared with its wild-type counterparts due to the induction of apoptosis in KO cells. Gene expression analysis of inducible heat-shock proteins (HSP70.1, HSP70.3, and HSP40) showed induction of these genes in KO cells early in the heat shock, but were drastically diminished at the later period of heat shock. Further analysis revealed that loss of ATE1 drastically reduced the stability of all three HSP mRNAs. These phenotypes were greatly restored by overexpression of Ate1 in KO cells. Our findings show that arginylation plays a protective role during heat stress by regulating HSP gene expression and mRNA stability.

Synergism of co-delivered nanosized antioxidants displayed enhanced anticancer efficacy in human colon cancer cell lines

“…Among them NP (10 μg/mL) treated cells showed maximum number of apoptotic/necrotic cells. The staining images for each group were analyzed by NIH ImageJ software (USA) [57] , [58] . Fig.…”

“…The apoptosis/necrosis was observed by fluorescence images in upright microscope (Nikon Eclipse 80i equipped with Nikon DS-Ri1 12.7 megapixel camera, Japan). For each group, all cells in four image frames were analyzed using NIH ImageJ analysis software (USA) by following literature reports [57] , [58] . Green stained cells were counted as live cells and bright orange/red stained cells were counted as apoptotic/necrotic cells.…”

“…Green stained cells were counted as live cells and bright orange/red stained cells were counted as apoptotic/necrotic cells. Percent (%) apoptotic cells were measured for each group [57] .…”

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

“…These differences imply that ATE1 may act as a scavenger of oxidatively damaged proteins in stress response. Also, the broad interactions between ate1 and many transcription regulators and histone modulators may help to elucidate the observed but unexplained effects of ATE1 on global transcriptional landscape (Lee et al, 2012;Eisenach et al, 2014;Deka et al, 2016). Particularly, many genes of histone modulators appear to have a phenotypesuppression relationship with ate1.…”

Multiple competing RNA structures dynamically control alternative splicing in human ATE1 gene

“…It is mediated by the arginyl transferase encoded within Ate1 gene (2). Ate1 is essential in most eukaryotic systems and is implicated in regulation of many physiological pathways including proteolysis (3,4), response to stress and heat shock (5)(6)(7), embryogenesis (8)(9)(10), regenerative processes (11)(12)(13), and aging (14,15). Ate1 has recently been identified as a master regulator affecting disease-associated pathways (16)(17)(18), and its knockout results in embryonic lethality and severe developmental defects in mice (9,10,19,20).…”