Ask about this productRelated genes to: MBNL2 Blocking Peptide
- Gene:
- MBNL2 NIH gene
- Name:
- muscleblind like splicing regulator 2
- Previous symbol:
- -
- Synonyms:
- MBLL, MBLL39
- Chromosome:
- 13q32.1
- Locus Type:
- gene with protein product
- Date approved:
- 2003-03-05
- Date modifiied:
- 2016-10-05
Related products to: MBNL2 Blocking Peptide
Related articles to: MBNL2 Blocking Peptide
- RNA-binding motif protein 20 (RBM20) is a splicing factor that forms discrete nuclear speckles. Certain pathogenic RBM20 variants disrupt its nuclear localization, leading to cytoplasmic granules formation. The composition of RBM20 nuclear speckles and cytoplasmic granules, how these compartments differ from one another, and how they contribute to splicing regulation remain unclear. Here, we employed in situ proximity labeling proteomics and identified 25 and 12 proteins associated with RBM20 nuclear speckles and cytoplasmic granules, respectively. RBM20 nuclear speckles were enriched in proteins involved in splicing and transcriptional regulation, whereas cytoplasmic granules contained proteins commonly found in other cytoplasmic granule populations. Among these, CELF1 and MBNL2 were detected in both RBM20 nuclear speckles and cytoplasmic granules, as confirmed by co-localization and immunoprecipitation experiments. We further showed that CELF1- and MBNL2-regulated splicing events were disrupted in the hearts of mice carrying pathogenic Rbm20 variants but not in animals with Rbm20 loss-of-function that lack cytoplasmic granules. Moreover, reducing cytoplasmic granule burden through RBM20 knockdown in pathogenic variant knock-in mice showed a trend toward partial restoration of MBNL2-mediated splicing defects. Collectively, these findings define the distinct protein compositions of RBM20 nuclear speckles and cytoplasmic granules and suggest that cytoplasmic RBM20 granules affect the splicing of non-RBM20 target genes. - Source: PubMed
Zhang YanghaiGregorich Zachery RLiu ChunlingLarson Eli JGe YingGuo Wei - Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are multisystemic diseases caused by the expression of toxic expansion RNAs that sequester muscleblind-like (MBNL) proteins, resulting in extensive alternative splicing dysregulation. Given that there are no current disease-modifying treatments for DM, we sought to identify compounds that rescue the underlying splicing dysregulation. A medium throughput splicing screen utilizing DM1 patient-derived fibroblasts was developed and used to screen 1584 compounds from the NIH NCI Diversity Set VI, leading to the identification of macbecin II, an HSP90 inhibitor. Macbecin II-mediated HSP90 inhibition corrects several MBNL-regulated splicing events in DM1 myotubes, and a structurally distinct HSP90 inhibitor, CCT018159, produces similar effects. Using RT-PCR splicing analysis, siRNA knockdown, RT-qPCR, immunoblotting, and RNA fluorescence in situ hybridization we examined the effects of HSP90 inhibition in DM models. HSP90 inhibition increases MBNL1 and MBNL2 transcript levels, increases MBNL2 protein, and reduces toxic CUG RNA and nuclear foci in DM1 cell models. An analysis of individual HSP90 isoforms reveals that knocking down HSP90AA1, HSP90AB1, and TRAP1 partially improves splicing defects, whereas HSP90B1 knockdown exacerbates mis-splicing. We also show that treatment with HSP90 inhibitors corrects mis-splicing in DM2 myotubes. Together, these data identify HSP90 as a modifier of RNA toxicity and alternative splicing in DM and support further evaluation of HSP90-directed therapeutic strategies. - Source: PubMed
Publication date: 2026/07/22
Zhang JingMascorro AmyOishi HumayraAliyeva AsmarShaughnessy SharonSheng JiaReddy KaalakCleary John DouglasBerglund J Andrew - Myotonic Dystrophy type 1 (DM1) is an autosomal multisystem disorder manifested due to unstable CTG nucleotide repeat expansion within the 3'-untranslated region of the dystrophia myotonica protein kinase () gene. Although progress towards understanding of molecular pathogenesis in muscle and heart has been made, the pathways that affect the brain in DM1 is fundamentally unknown. In addition, the congenital DM1 manifest even more complicated brain abnormalities. Despite the wealth of existing cellular and animal models, iPSCs based studies are being fostered as they replicate the human model more closely to the disease. In view of this context, we set out to characterize the differentiation potential of congenital DM1 patient derived iPSC lines towards neuronal cells. Using neurogenin2 (NGN2) induced direct reprogramming of iPSCs into neurons and chemically defined media-induced neural induction protocol, we find that congenital DM1 mutant iPSC derived neurons exhibited precocious differentiation, as evidenced by their expression of pan-neuronal markers TUJ1 and Map2, along with increased processes extension and neurite length. Moreover, unbiased RNA sequencing analyses and qPCR validation revealed precocious and enhanced expression of several neurogenic transcription factors including, Ascl1, NeuroG2, and NeuroD1. Furthermore, immunofluorescence imaging of MBNL1 and MBNL2, RNA-splicing factors, displayed enhanced nuclear aggregations, a hallmark of the DM1 disease, in the mutant lines. Moreover, investigation of RNA splicing events identified mis-splicing in many important genes/transcripts including RMST, ANK3 and MBD1 during the neural conversion of congenital DM1 lines. These studies reveal novel paradigms that may contribute to neurological pathogenesis in CDM1 patients. These studies also provide a strong foundation for future mechanistic investigation aimed at understanding CDM1 pathology and may open new avenues for the development of gene therapy approaches for individuals with DM1. - Source: PubMed
Publication date: 2026/07/01
Thumu Surya Chandra RaoGonzales Jean PatrickMunir SohaTuck ConnorDominguez OscarSingh Sandeep K - Muscleblind-like (MBNL) RNA-binding proteins (RBPs) possess modular domains that mediate regulation of alternative splicing and RNA localization. In Myotonic Dystrophy Type 1, a CTG repeat expansion disorder, MBNL is sequestered into intranuclear RNA foci, impairing its function. Previous studies found that MBNL self-associates through its exon 7, but the nature of this interaction is not well understood. We identified a cysteine in MBNL1 exon 7 that enables dimerization through the formation of an intermolecular disulfide bond. We likewise demonstrate that MBNL2 dimerizes by forming disulfide bonds between multiple cysteines in its carboxy-terminus. Nucleocytoplasmic fractionation revealed a greater proportion of MBNL1 dimer in the nucleus, suggesting a nuclear function for the MBNL1 dimer. We investigated a connection between MBNL1 dimerization and MBNL1-mediated regulation of alternative splicing. To accomplish this, we mutated the MBNL1 cysteine in question to alanine (C325A) and performed RNAseq. We uncovered novel splicing events sensitive to MBNL1 dimerization. We also found that MBNL1 C325A, when co-expressed with expanded CTG repeats, produces smaller, more numerous foci, suggesting a role for the MBNL1 dimer in maintaining foci integrity. These results provide insight into biological and pathological mechanisms of MBNL1 dimerization and suggest that other RBPs might similarly dimerize to regulate function. - Source: PubMed
Knudson Luke AKosti AdamHildebrandt Ryan PJennings EthanZhou Eric XMoss Kathryn RShi LiangNguyen GiaLinh NJanusz-Kaminska AleksandraWang Eric TBassell Gary J - Chemotherapy drug-induced changes of gene expression in the dorsal root ganglion (DRG) are critical for the genesis of chemotherapy-induced neuropathic pain (CINP). However, the mechanisms driving these changes remain elusive. Here, we report the downregulation of muscleblind-like protein 2 (MBNL2), an RNA-binding protein, in the DRG neurons after intraperitoneal injection of paclitaxel. Rescuing this downregulation blocks an increase of the C-C chemokine receptor type 2 (CCR2) in the DRG and mitigates paclitaxel-induced mechanical allodynia, heat and cold hyperalgesia and ongoing pain. Conversely, DRG downregulation of MBNL2 increases the expression of CCR2 in the DRG neurons and leads to CINP-like symptoms in naïve mice. Mechanistically, paclitaxel-induced downregulation of MBNL2 reduces its binding to the 3'-untranslated region of Ccr2 mRNA, thereby enhancing the stability of Ccr2 mRNA in the DRG. Given that MBNL2 and CCR2 are co-expressed in DRG neurons, these findings suggest that MBNL2 alleviates CINP, likely by destabilizing CCR2 expression in the DRG, and may represent a promising therapeutic strategy for this condition. - Source: PubMed
Publication date: 2026/04/11
Yan KeshiMa RuiningWang BingFeng XiaozhouLi XinjuMeng XiangleiShang HuijieKidd Benjamin MSwanson Maurice SHu HuijuanTao Yuan-Xiang