CUGBP1 and MBNL1 preferentially bind to 3′ UTRs and facilitate mRNA decay

Matsubara, Akio; Andersen, Henriette Skovgaard; Doktor, Thomas Koed; Okamoto, Takahiro; Ito, Mikako; Andresen, Brage S.; Ohno, Kinji

doi:10.1038/srep00209

Cited by 157 publications

(193 citation statements)

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“…Although the molecular pathology of DM1 is not well understood, the basic genetic defect is the presence of an expanded CTG repeat in the DMPK1 gene, leading to the formation of pre--mRNA foci containing CUG repeats in the nucleus of the cell (CUG exp RNA foci). These repeats accumulate the MBNL1 protein, an important alternative splicing factor that has recently also been implicated in the localization of mature mRNAs in the cytoplasm [8] and in regulation of mRNA decay [30]. It is proposed that the accumulation of MBNL1 in nuclear CUG exp RNA foci results in sufficient sequestration of nuclear MBNL1 to disrupt its normal function in regulating complex patterns of alternative splicing, resulting in aberrant splicing of a number of transcripts and ultimately leading to DM1 pathology [31--33].…”

Section: Discussionmentioning

confidence: 99%

“…While this is a distinct contrast to the behavior of well--studied splicing factors such as SC--35 and ASF/SF2 that migrate to rounded--up speckles in transcriptionally inhibited cells [27,28], it may well reflect the diverse roles proposed for MBNL1 in cellular RNA metabolism. MBNL1 has recently been implicated in mRNA decay [30] and in the sub--cellular localization of mature mRNAs, particularly those associated with cellular membranes and synapses [8]. In transcriptionally inhibited cells, the nuclear role for MBNL1 in splicing will be redundant, but its roles in other areas of RNA metabolism will persist.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptionally correlated subcellular dynamics of MBNL1 during lens development and their implication for the molecular pathology of myotonic dystrophy type 1

Coleman

Prescott

Sleeman

2014

Biochemical Journal

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11 Abbreviations: ASF, alternative splicing factor; 5-BrU, 5-bromouridine; Cy5, cyanine 5; DM1, Myotonic Dystrophy Type 1; DMEM, Dulbecco's modification of Eagle's medium; DMPK, dystrophia myotonica protein kinase; DRB 5,6--Dichloro--1--β--D--ribofuranosylbenzimidazole; FISH, fluorescent in situ hybridization; HLE, human lens epithelial; LEC, lens epithelial cell; MBNL1, muscleblind-like protein 1; PAGFP, photoactivatable GFP; PFA, paraformaldehyde; SC35, splicing component 35kDa; snoRNP, small nucleolar ribonucleoprotein; snRNP, small nuclear ribonucleoprotein; SSA, spliceostatin A; SSC, saline sodium citrate.2 Abstract Myotonic Dystrophy Type 1 (DM1) is caused by elongation of a CTG repeat in the dystrophia myotonica protein kinase (DMPK) gene. mRNA transcripts containing the resulting CUG exp repeats form accumulations, or foci, in the nucleus of the cell. The pathogenesis of Myotonic dystrophy type 1 (DM1) is proposed to result from inappropriate patterns of alternative splicing caused by sequestration of the developmentally regulated alternative splicing factor muscleblind--like 1 (MBNL1), by these foci. Since eye lens cataract is a common feature of DM1 we have examined the distribution and dynamics of MBNL1 in lens epithelial cell lines derived from DM1 patients. The results demonstrate that only a small proportion of nuclear MBNL1 accumulates in CUG exp pre--mRNA foci. MBNL1 is, however, highly mobile and changes sub--cellular localization in response to altered transcription and splicing activity. Moreover, immunolocalization studies in lens sections suggest that a change in MBNL1 distribution is important during lens growth and differentiation. While these data suggest that loss of MBNL1 function due to accumulation in foci is an unlikely explanation for DM1 symptoms in the lens, they do demonstrate a strong relationship between sub--cellular MBNL1 localisation and pathways of cellular differentiation, providing an insight into the sensitivity of the lens to changes in MBNL1 distribution.Short title: MBNL1 dynamics in lens epithelial cells from myotonic dystrophy patients Summary Statement: In eye lens cells from DM1 patients MBNL1 sequestration to RNA foci appears not to be a major pathological event. MBNL1 does, however, show clear changes in sub--cellular distribution related to transcriptional activity and cellular differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transcriptionally correlated subcellular dynamics of MBNL1 during lens development and their implication for the molecular pathology of myotonic dystrophy type 1

Coleman

Prescott

Sleeman

2014

Biochemical Journal

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“…MBNL functional inactivation in DM1 tissues results in the re-emergence of developmentally immature AS and alternative polyadenylation (APA) patterns in adult tissues as well as alterations in RNA localization and turnover (Masuda et al 2012;Wang et al 2012;Batra et al 2014). Since disruption of RNA processing is a prominent feature of DM1, in this study, we tested the possibility that similar molecular mechanisms contribute to disease manifestations in CDM.…”

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confidence: 99%

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

et al. 2017

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Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTG exp ) disorder caused by expression of CUG exp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUG exp -associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.

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“…It preferentially binds to GU-rich elements located in the 5′ and 3′ untranslated regions (UTRs), as well as in mRNA coding regions [15,16]. The association of CUGBP1 with its mRNA targets influences their alternative splicing, translation and turnover [17].…”

Section: Introductionmentioning

confidence: 99%

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

Zhai

Yang

et al. 2016

Diabetologia

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Aims/hypothesis CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain-and loss-of-function experiments and to further decipher the underlying molecular mechanisms. Methods A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared. Pancreas-specific CUGBP1 overexpression and knockdown mice were generated. Different lengths of the phosphodiesterase subtype 3B (PDE3B) 3′ untranslated region (UTR) were cloned for luciferase reporter analysis. Purified CUGBP1 protein was used for gel shift experiments.Results CUGBP1 is present in rodent islets and in beta cell lines; it is overexpressed in the islets of diabetic mice. Compared with control mice, the plasma insulin level after a glucose load was significantly lower and glucose clearance was greatly delayed in mice with pancreas-specific CUGBP1 overexpression; the opposite results were obtained upon pancreas-specific CUGBP1 knockdown. Glucose-and glucagon-like peptide1 (GLP-1)-stimulated insulin secretion was significantly attenuated in mouse islets upon CUGBP1 overexpression. This was associated with a strong decrease in intracellular cAMP levels, pointing to a potential role for cAMP PDEs. CUGBP1 overexpression had no effect on the mRNA levels of PDE1A, 1C, 2A, 3A, 4A, 4B, 4D, 7A and 8B subtypes, but resulted in increased PDE3B expression. CUGBP1 was found to directly bind to a specific ATTTGTT sequence residing in the 3′ UTR of PDE3B and stabilised PDE3B mRNA. In the presence of the PDE3 inhibitor cilostamide, glucose-and GLP-1-stimulated insulin secretion was no longer reduced by CUGBP1 overexpression. Similar to CUGBP1, PDE3B was overexpressed in the islets of diabetic mice. Conclusions/interpretation We conclude that CUGBP1 is a critical regulator of insulin secretion via activating PDE3B. Repressing this protein might provide a potential strategy for treating type 2 diabetes.

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CUGBP1 and MBNL1 preferentially bind to 3′ UTRs and facilitate mRNA decay

Cited by 157 publications

References 53 publications

Transcriptionally correlated subcellular dynamics of MBNL1 during lens development and their implication for the molecular pathology of myotonic dystrophy type 1

Transcriptionally correlated subcellular dynamics of MBNL1 during lens development and their implication for the molecular pathology of myotonic dystrophy type 1

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

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