Biology subjects

Ko, S.-H.

Publications and source records attributed to Ko, S.-H..

5 recordsLinked to original sources

bioRxiv2024

CELF2 promotes tau exon 10 inclusion via hinge domain-mediated nuclear condensation

Alternative splicing is a fundamental process that contributes to the functional diversity and complexity of proteins. The regulation of each alternative splicing event involves the coordinated action of multiple RNA-binding proteins, creating a diverse array of alternatively spliced products. Dysregulation of alternative splicing is associated with various diseases, including neurodegeneration. Here we demonstrate that CELF2, a splicing regulator and a GWAS-identified risk factor for Alzheimers disease, binds to mRNAs associated with neurodegenerative diseases, with a specific interaction observed in the intron adjacent to exon 10 on Tau mRNA. Loss of CELF2 in the mouse brain results in a decreased inclusion of Tau exon 10, leading to a reduced 4R:3R ratio. Further exploration shows that the hinge domain of CELF2 possesses an intrinsically disordered region (IDR), which mediates CELF2 condensation and function. The functionality of IDR in regulating CELF2 function is underscored by its substitutability with IDRs from FUS and TAF15. Using TurboID we identified proteins that interact with CELF2 through its IDR. We revealed that CELF2 co-condensate with NOVA2 and SFPQ, which coordinate with CELF2 to regulate the alternative splicing of Tau exon 10. A negatively charged residue within the IDR (D388), which is conserved among CELF proteins, is critical for CELF2 condensate formation, interactions with NOVA2 and SFPQ, and function in regulating tau exon 10 splicing. Our data allow us to propose that CELF2 regulates Tau alternative splicing by forming condensates through its IDR with other splicing factors, and that the composition of the proteins within the condensates determines the outcomes of alternative splicing events.

molecular biology↗

bioRxiv2024

Neutralization activity in chronic HIV infection is characterized by a distinct programming of follicular helper CD4 T cells

A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these antibodies are poorly understood. Here, we explored LN-associated histological, immunological, and virological mechanisms of bNAb generation in a cohort of anti-retroviral therapy (ART)-naive PLWH. We found that participants who produce bNAbs, termed neutralizers, have a superior LN-associated B cell follicle architecture compared with PLWH who do not. The latter was associated with a significantly higher in situ prevalence of Bcl-6hi follicular helper CD4 T cells (TFH), expressing a molecular program that favors their differentiation and stemness, and significantly reduced IL-10 follicular suppressor CD4 T cells. Furthermore, our data reveal possible molecular targets mediating TFH-B cell interactions in neutralizers. Together, we identify cellular and molecular mechanisms that contribute to the development of bNAbs in PLWH.

immunology↗

bioRxiv2023

Anti-muscle Atrophy Effects of Lactobacillus reuteri ATG-F4 and Its Impact on Intestinal Microbiota and Metabolites: Implications for Prophylaxis and Therapy

Lactobacillus reuteri ATG-F4, human gut-derived bacteria, was orally administrated in a model of hindlimb immobilization and confirmed the muscular performance, muscle mass and mechanism on anti-atrophy study. Concomitantly, the changes in the intestinal flora, the metabolites and cytokines were investigated. In the stapled immobilization mice model, ATG- F4 treated group had significantly increased muscle mass, myofiber size, running time to be exhausted and grip strength. The cytokine levels in serum and muscle tissues were reduced by ATG-F4 treatment. Furthermore, the phosphorylation of proteins involved in muscle synthesis such as mTOR, p70S6K, rpS6 and 4E-BP1 increased and MuRF1 related to muscle atrophy factor reduced in the TA and GA muscles. ATG-F4 treatment changed the ratio of main intestinal microflora by increasing the family Muribaculaceae (phylum Bacteroidetes) and decreasing the family Lachnospiraceae (phylum Firmicutes) and Lactobacillaceae (phylum Firmicutes). Also, the level of short chain fatty acids (SCFAs) including butyric acid and acetic acid in the serum of ATG-F4 group were increased. These results suggest that L. reuteri ATG- F4 can inhibit muscle atrophy and it is associated with the microbiota and its metabolites with the anti-inflammation effect. ATG-F4 may be a potential prophylactic or therapeutic composition for muscle atrophy.

physiology↗

bioRxiv2022

Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

Transcription factors (TFs) activate enhancers to drive cell-specific gene programs in response to signals, but our understanding of enhancer assembly during signaling events is incomplete. Here, we show that Androgen Receptor (AR), a steroid hormone-regulated transcription factor, forms condensates through multivalent interactions in response to androgen signaling to orchestrate enhancer assembly. We demonstrate that the intrinsically disordered N-terminal domain (NTD) of AR drives 1,6-Hexanediol-sensitive condensate formation and that NTD deletion or aromatic residue mutation reduces AR self-association and abolishes AR transcriptional activity. AR NTD can be substituted by intrinsically disordered regions (IDRs) from selective proteins for AR condensation capacity and transactivation function. Surprisingly, strengthened AR condensation capacity caused by extending the polyQ tract within AR NTD also leads to impaired transcriptional activity without affecting AR binding on enhancers. Furthermore, either NTD deletion or polyQ extension reduces heterotypic multivalent interactions between AR and other enhancer components. These results suggest the importance of an optimal level of AR condensation in mediating AR-AR homotypic and AR-cofactor heterotypic interactions to regulate enhancer assembly in response to signals. Our study supports the notion that alteration of the fine-tuned multivalent IDR-IDR interactions might underlie AR-related human pathologies, thereby providing novel molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR multivalent interactions.

molecular biology↗

bioRxiv2020

Association between toothbrushing and non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. Periodontitis, as chronic inflammatory destructive disease, is associated metabolic syndomes bidirectionally. Toothbrushing is an essential and important way to manage periodontitis through mechanical removal of biofilm at periodontal tissue. We aimed to assess the association between toothbrushing frequency and the prevalent NAFLD in nationally representative Korean adults. Among adults aged 19 years and older who participated in the Korea National Health and Nutrition Examination Survey in 2010, a total of 6,352 subjects were analyzed. NAFLD was defined as fatty liver index [≥]60. Multiple logistic regression analysis was used to estimate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). An inverse association between toothbrushing frequency and NAFLD was found. The adjusted ORs (95% CIs) of NALFD was 0.56 (0.35 - 0.90) in the group who performed toothbrushing [≥] 3 per day compared to the group that performed toothbrushing [≤] 1 per day. For those with toothbrushing frequency [≤]1 per day, the adjusted OR (95% CIs) of NAFLD was 2.27 (1.22-4.23) in smokers and 4.55 (1.98 - 10.44) in subjects with diabetes mellitus (DM), compared to those without the disease and with toothbrushing frequency [≥]2 per day, respectively. Our results indicate that higher frequency of toothbrushing is inversely associated with NAFLD. As a modifiable oral habit, regular toothbrushing may be recommended to lower risk of NAFLD, especially in high risk groups such as smokers and diabetic patients.

scientific communication and education↗