Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation

Abstract

Ataxin-2 is a cytoplasmic protein, product of the ATXN2 gene, whose deficiency leads to obesity, while its gain-of-function leads to neural atrophy. Ataxin-2 affects RNA homeostasis, but its effects are unclear. Here, immunofluorescence analysis suggested that ataxin-2 associates with 48S pre-initiation components at stress granules in neurons and mouse embryonic fibroblast, but is not essential for stress granule formation. Coimmunoprecipitation analysis showed associations of ataxin-2 with initiation factors, which were concentrated at monosome fractions of polysome gradients like ataxin-2, unlike its known interactor PABP. Mouse embryonic fibroblasts lacking ataxin-2 showed increased phosphorylation of translation modulators 4E-BP1 and ribosomal protein S6 through the PI3K/mTOR pathways. Indeed, human neuroblastoma cells after trophic deprivation showed a strong induction of ATXN2 transcript via mTOR inhibition. Our results support the notion that ataxin-2 is a nutritional stress-inducible modulator of mRNA translation at the pre-initiation complex.

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

“…Ataxin-2 is considered a cytoplasmic protein that is localised at the rough endoplasmic reticulum (rER) [124]. The globular domains (Lsm and LsmAD) are two regions that are highly conserved in proteins thought to be involved the process of RNA metabolism, such as splicing and modification [125,126]. The Lastres-Becker et al study, found that when starved, mouse and human ataxin-2, was able to modulate translational control at the pre-initiation complex via PI3K/mTOR pathways [125].…”

“…The globular domains (Lsm and LsmAD) are two regions that are highly conserved in proteins thought to be involved the process of RNA metabolism, such as splicing and modification [125,126]. The Lastres-Becker et al study, found that when starved, mouse and human ataxin-2, was able to modulate translational control at the pre-initiation complex via PI3K/mTOR pathways [125]. This study highlights another possible major function of ataxin-2, its ability to regulate some metabolic activity with a study in C. elegans showing that down regulation of the ataxin-2 homolog leads to fat storage and an increase in growth.…”

PINK1 and Ataxin-2 as modifiers of growth

“…They confirmed that Pbp1 as the yeast orthologue of Ataxin-2 is being controlled by AMP-kinase phosphorylation signals. Human Ataxin-2 is transcriptionally induced during starvation, and the Ataxin-2 protein relocalizes to stress granules in periods of glucose deprivation or oxidative stress [6, 7]. Downstream effects of Ataxin-2 include the repression of mTOR-dependent phosphorylation signals, but also the enhancement of PINK1-dependent phosphorylation signals [1, 6–8].…”

“…Human Ataxin-2 is transcriptionally induced during starvation, and the Ataxin-2 protein relocalizes to stress granules in periods of glucose deprivation or oxidative stress [6, 7]. Downstream effects of Ataxin-2 include the repression of mTOR-dependent phosphorylation signals, but also the enhancement of PINK1-dependent phosphorylation signals [1, 6–8]. Via Ataxin-2 occurs also a regulation of the cell size, of the availability of lipid and glycogen stores as alternative fuels in times of high bioenergetic demands, and of ribosomal translation during stress periods [6, 8].…”

“…Downstream effects of Ataxin-2 include the repression of mTOR-dependent phosphorylation signals, but also the enhancement of PINK1-dependent phosphorylation signals [1, 6–8]. Via Ataxin-2 occurs also a regulation of the cell size, of the availability of lipid and glycogen stores as alternative fuels in times of high bioenergetic demands, and of ribosomal translation during stress periods [6, 8]. These latter global effects of Ataxin-2 are canonical functions of the mTORC1 signaling complex.…”