Ataxin-2-Like Is a Regulator of Stress Granules and Processing Bodies

Abstract

Paralogs for several proteins implicated in neurodegenerative disorders have been identified and explored to further facilitate the identification of molecular mechanisms contributing to disease pathogenesis. For the disease-causing protein in spinocerebellar ataxia type 2, ataxin-2, a paralog of unknown function, termed ataxin-2-like, has been described. We discovered that ataxin-2-like associates with known interaction partners of ataxin-2, the RNA helicase DDX6 and the poly(A)-binding protein, and with ataxin-2 itself. Furthermore, we found that ataxin-2-like is a component of stress granules. Interestingly, sole ataxin-2-like overexpression led to the induction of stress granules, while a reduction of stress granules was detected in case of a low ataxin-2-like level. Finally, we observed that overexpression of ataxin-2-like as well as its reduction has an impact on the presence of microscopically visible processing bodies. Thus, our results imply a functional overlap between ataxin-2-like and ataxin-2, and further indicate a role for ataxin-2-like in the regulation of stress granules and processing bodies.

Herpes simplex virus ICP27 regulates alternative pre-mRNA polyadenylation and splicing in a sequence-dependent manner

“…3B). ICP27 induced retention of four introns (16)(17)(18)(19) near the 3′ end of ATXN2L (ataxin-2-like), a regulator of stress granules that is also implicated in neurodegenerative disorders (26) (Fig. 3C).…”

Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson's disease pathogenesis

“…Ataxin-2 protein binds ribosomes [8] as well as the polyA binding protein cytoplasmic 1 (PABPC1) protein [9] that interacts with eIF4G, thereby favoring transcript circularization and translation initiation [10]. Ataxin-2 is also reported to interact with GW182 and Argonaute 1 (Ago1), two proteins involved in the biogenesis of miRNAs [11], and is also located in cellular compartments where protein translation occurs, such as P bodies [12] and rough endoplasmic reticulum [13]. Interestingly, some mutations in ATXN2 are associated with a PD phenotype, suggesting that disturbances in protein translation may contribute to PD pathogenesis.…”

PRMT1-mediated arginine methylation controls ATXN2L localization

“…First, DNA fragments encoding the N-terminal region of ATXN2L were PCR amplified using plasmid RSV-ATXN2L-MYC [24,25] as template and primer pair ATXN2L-EcoRI-fw (5 0 -GC GAATTCAG TTG AAG CCT CAG CCG CTA CAA CAG-3 0 ; EcoRI restriction site underlined) and ATXN2L-int-R361R-rev (5 0 -GCT GCA TCG AAC TCC TCC CCG GGG ACC-3 0 ) or ATXN2L-EcoRI-fw and ATXN2L-int-R361Q-rev (5 0 -GCT GCA TCG AAC TCC TCC CTG GGG ACC-3 0 ; modified triplets underlined). DNA fragments encoding the C-terminal region of ATXN2L were amplified using the primer pair ATXN2L-int-R370R-fw (5 0 -GTT CGA TGC AGC AGC TCT CGG GGC GGT-3 0 ) and ATXN2L-SalI-rev (5 0 -GTC GTCGAC TTA TTG GGG GTG TCC GAT GTA GGG GTA-3 0 ; SalI restriction site underlined) or ATXN2L-int-R370Q-fw (5 0 -GTT CGA TGC AGC AGC TCT CAG GGC GGT-3 0 ; modified triplets underlined) and ATXN2L-SalI-rev.…”

“…Methylation inhibition alters ATXN2L localization to nuclear splicing speckles ATXN2L is a predominantly cytoplasmic protein, but also localizes to nuclear splicing speckles [24]. Since protein methylation is known to modulate the localization of proteins [1,2], we examined next if ATXN2L localization is affected by its methylation state.…”

“…In our earlier study we report that the protein ataxin-2-like (ATXN2L), the paralog of ataxin-2 (ATXN2), which is implicated in the neurodegenerative disorder spinocerebellar ataxia type 2, is a component of SGs and further plays a role in the regulation of SG formation [24]. In addition to its potential role in the cellular mRNA metabolism, ATXN2L might function in cytokine signaling, since ATXN2L associates with the erythropoietin receptor myeloproliferative leukemia protein (MPL) [25].…”