Post‐translational protein arginylation in the normal nervous system and in neurodegeneration

Abstract

Post-translational arginylation of proteins is an important regulator of many physiological pathways in cells. This modification was originally noted in protein degradation during neurodegenerative processes, with an apparently different physiological relevance between central and peripheral nervous system. Subsequent studies have identified a steadily increasing number of proteins and proteolysis-derived polypeptides as arginyltransferase (ATE1) substrates, including b-amyloid, a-synuclein, and TDP43 proteolytic fragments. Arginylation is involved in signaling processes of proteins and polypeptides that are further ubiquitinated and degraded by the proteasome. In addition, it is also implicated in autophagy/ lysosomal degradation pathway. Recent studies using mutant mouse strains deficient in ATE1 indicate additional roles of this modification in neuronal physiology. As ATE1 is capable of modifying proteins either at the N-terminus or middle-chain acidic residues, determining which proteins function are modulated by arginylation represents a big challenge. Here, we review studies addressing various roles of ATE1 activity in nervous system function, and suggest future research directions that will clarify the role of post-translational protein arginylation in brain development and various neurological disorders.

Arginyltransferase ATE1 is targeted to the neuronal growth cones and regulates neurite outgrowth during brain development

“…Multiple studies over the years have implicated arginylation in neuronal function (Galiano et al, 2016). It has been suggested that arginylation facilitates nerve regeneration after injury (Wang and Ingoglia, 1997) and, more recently, participates in neural tube closure (Kim et al, 2016).…”

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

“…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).…”

“…In mammals, they differ by mutually exclusive choice between two adjacent, homologous 129-bp exons (7a or 7b), and by alternative choice of the initial exon (1a or 1b) (22). The two major mRNA isoforms of Ate1 are Ate1-1 (1b7a) and Ate1-2 (1b7b), and the isoforms that contain both exon 7a and 7b are suppressed by mutually exclusive splicing (18). In mice, Ate1-1 and Ate1-2 are expressed stably in all tissues, but their ratio varies from 0.1 in the skeletal muscle to 10 in the testis (21,23,24).…”

“…To date, the mechanism of MXE splicing of exons 7a and 7b in Ate1 has not been studied in detail (18). Generally, MXE clusters are believed to evolve through tandem genomic duplications (26)(27)(28), and many of them implement mutually exclusive splicing through a mechanism that depends on competing RNA structures (29).…”

Arginylation: a new regulator of mRNA stability and heat stress response

“…7, 8 Thus arginylation is emerging as a global regulator of cellular physiology by regulating cell survival to cell death. 9, 10 Cell survival in stressful conditions mainly depends on stress response pathways and involvement of arginylation has been reported in diverse stress conditions, including nitrosative stress, ER stress, and cytosolic misfolded protein stress. Oxidation of Cys residues upon nitrosative or oxidative stress and subsequent arginylation of oxidized Cys is reported to be a key regulatory mechanism during nitrosative and oxidative stress response.…”