Functions of the Muscleblind-like protein family and their role in disease

Figures

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  Fig. 1. Amino acid sequence and structural features of human MBNL family proteins. A, Schematic representation of the amino acid positions of the CCCH-type zinc finger motifs in human MBNL family proteins (MBNL1, MBNL2 and MBNL3). These zinc finger motifs are essential for RNA binding and functional regulation. B, Multiple sequence alignment of human MBNL1 (Homo sapiens, Hs; NCBI Reference Sequence: NP_001374715.1), MBNL2 (NCBI Reference Sequence: NP_001369579.1), and MBNL3 (NCBI Reference Sequence: NP_001373825.1). Conserved residues are highlighted, indicating regions of functional importance across the family. The sequence alignment was performed using the ESPript program [25]

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  Fig. 2. Major mechanisms of MBNL protein regulation

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  Fig. 3. Role of MBNL proteins in the pathogenesis of DM1 and DM2. This figure illustrates the pathological mechanisms involving MBNL proteins in myotonic dystrophy type 1 (DM1) and type 2 (DM2). In both conditions, expanded CUG or CCUG repeats in mutant transcripts sequester MBNL proteins into nuclear foci, reducing their availability for normal RNA processing. This sequestration disrupts alternative splicing, leading to the misregulation of multiple target transcripts and the manifestation of disease symptoms. Key mis-spliced targets are highlighted, including transcripts critical for muscle and heart function, contributing to the characteristic symptoms of DM1 and DM2

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  Fig. 4. Mechanistic diagram of the tumor suppressor function of MBNL1. This figure illustrates the multifaceted tumor suppressor roles of MBNL1 in different cancer-related processes

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  Fig. 5. Mechanistic diagram of the oncogenic function of MBNL1. Regulation of metabolic pathways (top left): MBNL1 promotes NTRK2 transcription by facilitating PAX5 binding to the promoter region of NTRK2 pre-mRNA. This, in turn, enhances aerobic glycolysis in glioblastoma (GBM), supporting tumor growth and metabolism. Angiogenesis facilitation (top right): MBNL1 is involved in promoting angiogenesis by influencing the VEGF and TGF-α signaling pathways. MBNL1 also regulates miR-130b-3p and STAT3 activity, which contribute to vascular development and cancer cell survival. Epigenetic and transcriptional regulation (center left): MBNL1 interacts with DOT1L, which influences histone methylation at MLL fusion target genes, enhancing their transcription. This activity is implicated in cancer cell proliferation. Alternative splicing and nuclear translocation (bottom center): MBNL1 regulates alternative splicing of cancer-related transcripts, including MAP2K7 exon 2, which activates JNK signaling and promotes cancer cell stemness and proliferation. Additionally, MBNL1 nuclear localization is critical for splicing regulation. Microenvironment and tumor cell invasion (bottom left): MBNL1 modulates…

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  Fig. 6. Mechanistic diagram of MBNL2 regulatory function in cancer. Autophagy and invasion (left panel): MBNL2, influenced by CCL2 from M2-TAMs, facilitates the degradation of Bcl-2 mRNA, leading to the activation of Beclin-1 and autophagy. This promotes tumor growth and invasion. Proliferation and migration (second panel): Under hypoxic conditions, MBNL2 upregulates VEGF-A expression, enhancing cancer cell proliferation and migration. Cell cycle regulation (middle panel): MBNL2 regulates the degradation of p21 mRNA, facilitating cell cycle progression by activating CHK1. This process is modulated by treatments such as camptothecin or MBNL2 siRNA/shRNA, which interfere with MBNL2 activity. Invasion and migration (second-to-right panel): MBNL2, modulated by miR-182, activates the PI3K/Akt pathway, promoting cancer cell invasion and migration. Metastasis (right panel): MBNL2 enhances metastasis by activating AKT and stabilizing the expression of key proteins such as vimentin, cofilin, and MMP2, which are involved in cytoskeletal remodeling and extracellular matrix degradation. This process can be targeted by neobractatin treatment. These mechanisms collectively highlight MBNL2’s central…

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  Fig. 7. Mechanistic diagram of MBNL3 promoting ovarian cancer progression. The pluripotent transcription factors NANOG, OCT4, SOX2 and TBP activate MBNL3 transcription, leading to its expression in cancer cells. MBNL3 regulates alternative splicing of lncRNA-PXN-AS1, generating two isoforms: lncRNA-PXN-AS1-L: stabilizes PXN mRNA and promotes its accumulation; and lncRNA-PXN-AS1-S: enhances the translation of PXN mRNA and raises the level of PXN protein, contributing to tumorigenesis and progression. This mechanistic understanding highlights MBNL3 as a key factor in regulating PXN expression through lncRNA-PXN-AS1 splicing and underscores its potential as a therapeutic target in ovarian cancer