RNA association and nucleocytoplasmic shuttling by ataxin-1

Irwin, Stuart; Vandelft, Mark; Pinchev, Deborah; Howell, Jenny L.; Graczyk, Joanna; Orr, Harry T.; Truant, Ray

doi:10.1242/jcs.01611

Cited by 112 publications

(119 citation statements)

References 47 publications

Supporting

Mentioning

110

Contrasting

Order By: Relevance

“…One explanation for this would be that aggregated protein trapped in nuclear inclusions may not function in the dynamic properties of ataxin-7 and hence cannot confer the toxic gainof-function related to the normal ataxin-7 activity of nuclear shuttling. We demonstrated that polyglutamine expansion in ataxin-7 could slow but not stop nuclear export dynamics of ataxin-7, consistent with similar FRAP experiments carried out on other polyglutamine disease proteins (52-54) but different from the block of nuclear export observed for ataxin-1 (39). The evidence for toxicity of polyglutamine proteins and aggregate formation is controversial, because recent data suggest that in the context of huntingtin, polyglutamine aggregation can be either innocuous (55) or even neuroprotective (19,56).…”

Section: Discussionsupporting

confidence: 88%

Ataxin-7 Can Export from the Nucleus via a Conserved Exportin-dependent Signal

Taylor

Grote

Xia

et al. 2006

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Spinocerebellar ataxia type 7 is a progressive neurodegenerative disorder caused by a CAG DNA triplet repeat expansion leading to an expanded polyglutamine tract in the ataxin-7 protein. Ataxin-7 appears to be a transcription factor and a component of the STAGA transcription coactivator complex. Here, using live cell imaging and inverted fluorescence recovery after photobleaching, we demonstrate that ataxin-7 has the ability to export from the nucleus via the CRM-1/exportin pathway and that ataxin-7 contains a classic leucine-type nuclear export signal (NES). We have precisely defined the location of this NES in ataxin-7 and found it to be fully conserved in all vertebrate species. Polyglutamine expansion was seen to reduce the nuclear export rate of mutant ataxin-7 relative to wildtype ataxin-7. Subtle point mutation of the NES in polyglutamine expanded ataxin-7 increased toxicity in primary cerebellar neurons in a polyglutamine length-dependent manner in the context of fulllength ataxin-7. Our results add ataxin-7 to a growing list of polyglutamine disease proteins that are capable of nuclear shuttling, and we define an activity of ataxin-7 in the STAGA complex of trafficking between the nucleus and cytoplasm. Spinocerebellar ataxia type 7 (SCA7)4 is a dominantly inherited neurodegenerative disorder characterized by loss of neurons in the cerebellum, brain stem, and retina (1). SCA7 is a member of a family of neurodegenerative diseases in which a CAG DNA triplet repeat expansion results in polyglutamine expansion in the gene product (2). Other members of this polyglutamine expansion disease family include Huntington disease, spinobulbar muscle atrophy, dentatorubral pallidoluysian atrophy, and spinocerebellar ataxia types 1, 2, 3, 6, and 17 (3, 4). One unique feature of SCA7 is the loss of photoreceptor neurons in the retina leading to cone-rod dystrophy (5). The mutant ataxin-7 protein can have polyglutamine repeats from 38 to 300 residues in length (6). Ataxin-7 subcellular localization has been seen to be primarily nuclear with nuclear import signals (NLSs) defined in both the central (7), and carboxyl-terminal regions of the protein (8). Within the nucleus, ataxin-7 is known to be a subunit of the mammalian GCN5 histone acetyltransferase STAGA transcription coactivator complex (9). Ataxin-7 directly binds GCN5, and mutant ataxin-7 can inhibit the histone acetyltransferase activity of STAGA (10). Although the precise biological function of ataxin-7 is unknown, mutant ataxin-7 is known to interfere with Crx-dependent transcription of retinal photoreceptor-specific genes (11, 12). Ataxin-7 interacts with TFTC/STAGA protein subunits through a central evolutionarily conserved block of residues that have defined an ataxin-7 homology family in species ranging from human to yeast (9). In Saccharomyces cerevisiae, the yeast ataxin-7 homolog, Sgf73, is a member of the SAGA and SLIK histone acetyltransferase complexes (13). Ataxin-7 and the Crx homeodomain transcription factor interact via glutamine regions in each p...

show abstract

Section: Discussionsupporting

confidence: 88%

Ataxin-7 Can Export from the Nucleus via a Conserved Exportin-dependent Signal

Taylor

Grote

Xia

et al. 2006

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Overexpression of miR-101b in NIH3T3 cells leads to a reduction of both these proteins, and to a reduced luciferase activity of ATXN1, or STC1 gene 3 0 -UTR-based reporter constructs. ATXN1 is an RNAbinding protein thought to act as a transcriptional repressor (Yue et al, 2001;Irwin et al, 2005). The expression of pathogenic ATXN1 protein carrying expanded tracts of polyQ results in Spinocerebellar Ataxia type 1 (SCA1), a disease that decimates cerebellar Purkinje cells and brain stem neurons (Skinner et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Regulation of microRNA expression by HMGA1 proteins

et al. 2009

View full text Add to dashboard Cite

The High Mobility Group proteins HMGA1 are nuclear architectural factors that play a critical role in a wide range of biological processes. Since recent studies have identified the microRNAs (miRNAs) as important regulators of gene expression, modulating critical cellular functions such as proliferation, apoptosis and differentiation, the aim of our work was to identify the miRNAs that are physiologically regulated by HMGA1 proteins. To this purpose, we have analysed the miRNA expression profile of mouse embryonic fibroblasts (MEFs) carrying two, one or no Hmga1 functional alleles using a microarray (miRNA microarray). By this approach, we found a miRNA expression profile that differentiates Hmga1-null MEFs from the wild-type ones. In particular, a significant decrease in miR-196a-2, miR-101b, miR-331 and miR-29a was detected in homozygous Hmga1-knockout MEFs in comparison with wild-type cells. Consistently, these miRNAs are downregulated in most of the analysed tissues of Hmga1-null mice in comparison with the wild-type mice. ChIP assay shows that HMGA1 is able to bind regions upstream of these miRNAs. Moreover, we identified the HMGA2 gene product as a putative target of miR-196a-2, suggesting that HMGA1 proteins are able to downregulate the expression of the other member of the HMGA family through the regulation of the miR-196a-2 expression. Finally, ATXN1 and STC1 gene products have been identified as targets of miR-101b. Therefore, it is reasonable to hypothesize that HMGA1 proteins are involved in several functions by regulating miRNA expression.

show abstract

“…However, their function in the nucleus is not fully understood. Using a live-cell nucleocytoplasmic transport assay, it was shown that wildtype, but not polyglutamine expanded mutant ataxin-1, has the ability to export from the nucleus [22,23]. Therefore, it is possible that in SCA1 mice TG2 is translocated to the nucleus [13] due to retention of mutant ataxin-1 within Purkinje cell nuclei.…”

Section: Discussionmentioning

confidence: 99%

Role of tissue transglutaminase type 2 in calbindin–D28k interaction with ataxin-1

Vig

Wei

Shao

et al. 2007

Neuroscience Letters

View full text Add to dashboard Cite

Spinocerebellar ataxia-1 (SCA1) is caused by the expansion of a polyglutamine repeats within the disease protein, ataxin-1. The mutant ataxin-1 precipitates as large intranuclear aggregates in the affected neurons. These aggregates may protect neurons from mutant protein and/or trigger neuronal degeneration by encouraging recruitment of other essential proteins. Our previous studies have shown that calcium binding protein calbindin-D28k (CaB) associated with SCA1 pathogenesis is recruited to ataxin-1 aggregates in Purkinje cells of SCA1 mice. Since our recent findings suggest that tissue transglutaminase 2 (TG2) may be involved in cross-linking and aggregation of ataxin-1, the present study was initiated to determine if TG2 has any role in CaB-ataxin-1 interaction. The guinea pig TG2 covalently cross-linked purified rat brain CaB. Time dependent progressive increase in aggregation produced large multimers, which stayed on top of the gel. CaB interaction with ataxin-1 was studied using HeLa cell lysates expressing GFP and GFP tagged ataxin-1 with normal and expanded polyglutamine repeats (Q2, Q30 and Q82). The reaction products were analyzed by Western blots using anti-polyglutamine, CaB or GFP antibodies. CaB interacted with ataxin-1 independent of TG2 as the protein-protein cross-linker DSS stabilized CaB-ataxin-1 complex. TG2 cross-linked CaB preferentially with Q82 ataxin-1. The cross-linking was inhibited with EGTA or TG2 inhibitor cystamine. The present data indicate that CaB may be a TG2 substrate. In addition, aggregates of mutant ataxin-1 may recruit CaB via TG2 mediated covalent cross-linking, further supporting the argument that ataxin-1 aggregates may be toxic to neurons.

show abstract

RNA association and nucleocytoplasmic shuttling by ataxin-1

Cited by 112 publications

References 47 publications

Ataxin-7 Can Export from the Nucleus via a Conserved Exportin-dependent Signal

Ataxin-7 Can Export from the Nucleus via a Conserved Exportin-dependent Signal

Regulation of microRNA expression by HMGA1 proteins

Role of tissue transglutaminase type 2 in calbindin–D28k interaction with ataxin-1

Contact Info

Product

Resources

About