A novel protein with RNA-binding motifs interacts with ataxin-2

Shibata, Hiroki

doi:10.1093/hmg/9.9.1303

Cited by 209 publications

(191 citation statements)

References 34 publications

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“…Previously, evidence has been provided that human ATXN2 plays a role in RNA-processing pathways (Shibata et al, 2000;Ralser et al, 2005a;Satterfield and Pallanck, 2006). Here, we present further data substantiating that ATXN2 takes part in important steps of mRNA control and regulation.…”

Section: Discussionsupporting

confidence: 78%

“…Initially, ATXN2 was identified to interact with the protein A2BP1 (ATXN2 binding protein 1) that contains RNA recognition motifs (Shibata et al, 2000). Along this line, it has been reported that ATXN2 contains an Like Sm (LSm) domain that might be capable of RNA binding as observed for other LSm domain proteins (Neuwald and Koonin, 1998;Achsel et al, 2001;Albrecht et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Nonhoff

Ralser

Welzel

et al. 2007

MBoC

309

320

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Tight control of translation is fundamental for eukaryotic cells, and deregulation of proteins implicated contributes to numerous human diseases. The neurodegenerative disorder spinocerebellar ataxia type 2 is caused by a trinucleotide expansion in the SCA2 gene encoding a lengthened polyglutamine stretch in the gene product ataxin-2, which seems to be implicated in cellular RNA-processing pathways and translational regulation. Here, we substantiate a function of ataxin-2 in such pathways by demonstrating that ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6, a component of P-bodies and stress granules, representing cellular structures of mRNA triage. We discovered that altered ataxin-2 levels interfere with the assembly of stress granules and cellular P-body structures. Moreover, ataxin-2 regulates the intracellular concentration of its interaction partner, the poly(A)-binding protein, another stress granule component and a key factor for translational control. Thus, our data imply that the cellular ataxin-2 concentration is important for the assembly of stress granules and P-bodies, which are main compartments for regulating and controlling mRNA degradation, stability, and translation. INTRODUCTIONAn essential step in the control of global gene expression in eukaryotes is the regulation of mRNA translation and degradation. Shortening of the poly(A) tail is the initial step to trigger mRNA for decay in two major mRNA degradation pathways in eukaryotic cells (Bernstein and Ross, 1989;Peltz et al., 1991;Decker and Parker, 1994;Beelman and Parker, 1995). In one pathway, the deadenylated mRNA is degraded by a cytoplasmic protein complex, the exosome, consisting of a number of exonucleases with 3Ј-5Ј activity (Butler, 2002). In the other pathway, shortening of the poly(A) tail leads to the removal of the cap structure of the mRNA by the decapping proteins DCP1 and DCP2 facilitating 5Ј-3Ј degradation of the mRNA through the exoribonuclease XRN1 (Beelman and Parker, 1995;Butler, 2002). These proteins colocalize in discrete cytoplasmic foci in mammalian cells, termed processing bodies or P-bodies (also known as DCP1-or GW182-bodies), indicating that mRNA decay is restricted to distinct cytoplasmic compartments in mammalian cells (van Dijk et al., 2002;Cougot et al., 2004). The human protein CCR4, which is involved in mRNA deadenylation, the decapping stimulating LSm proteins LSm1-7, the DEAD/Hbox RNA helicase DDX6 (also known as RCK/p54), GW182, and Ge-1 are components of P-bodies (Bouveret et al., 2000;Eystathioy et al., 2002;Ingelfinger et al., 2002; LykkeAndersen, 2002;Cougot et al., 2004;Yu et al., 2005). Moreover, the RNA-associated protein 55, hEDC3, Hedls as well as factors of the RISC complex localize to P-bodies in mammalian cells (Fenger-Gron et al., 2005;Liu et al., 2005;Sen and Blau, 2005;Yang et al., 2006). P-bodies represent dynamic structures that are in an equilibrium with polysomes and contain nontranslating mRNA . Remarkably, recent work demonstrated that mRNA molecules entering P-bodies can a...

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Nonhoff

Ralser

Welzel

et al. 2007

MBoC

309

320

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“…Previously, the only known interacting protein of RBFOX1 was Ataxin-2 (Shibata et al 2000), which is how RBFOX1 was first discovered. We did not find this protein in our analysis, probably because of its tissue-restricted expression.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2

Sun¹,

Zuo²,

Fregoso³

et al. 2011

RNA

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RBFOX1 and RBFOX2 are alternative splicing factors that are predominantly expressed in the brain and skeletal muscle. They specifically bind the RNA element UGCAUG, and regulate alternative splicing positively or negatively in a position-dependent manner. The molecular basis for the position dependence of these and other splicing factors on alternative splicing of their targets is not known. We explored the mechanisms of RBFOX splicing activation and repression using an MS2-tethering assay. We found that the Ala/Tyr/Gly-rich C-terminal domain is sufficient for exon activation when tethered to the downstream intron, whereas both the C-terminal domain and the central RRM are required for exon repression when tethered to the upstream intron. Using immunoprecipitation and mass spectrometry, we identified hnRNP H1, RALY, and TFG as proteins that specifically interact with the C-terminal domain of RBFOX1 and RBFOX2. RNA interference experiments showed that hnRNP H1 and TFG modulate the splicing activity of RBFOX1/2, whereas RALY had no effect. However, TFG is localized in the cytoplasm, and likely modulates alternative splicing indirectly.

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“…The PAM2 domain is known to bind RNA. Ataxin‐2 has been observed to interact with A2BP1 (ataxin‐2‐binding protein 1), which might regulate RNA tissue‐specific alternative splicing 23. In addition, ataxin‐2 shows significant homology to the yeast protein Pbp1 (Pab1/PABP‐binding protein 1) that is involved in mRNA polyadenilation.…”

Section: Protein and Its Functionmentioning

confidence: 99%

The Multiple Faces of Spinocerebellar Ataxia type 2

Antenora

Rinaldi

Roca

et al. 2017

Ann Clin Transl Neurol

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Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin‐2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available. Although the functions of ataxin‐2 have not been completely elucidated, the protein is involved in mRNA processing and control of translation. Recently, it has also been shown that the size of the CAG repeat in normal alleles represents a risk factor for ALS, suggesting that ataxin‐2 plays a fundamental role in maintenance of neuronal homeostasis.

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A novel protein with RNA-binding motifs interacts with ataxin-2

Cited by 209 publications

References 34 publications

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2

The Multiple Faces of Spinocerebellar Ataxia type 2

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