Biology subjects

Bae, D.

Publications and source records attributed to Bae, D..

6 recordsLinked to original sources

bioRxiv2025

Fusobacterium nucleatum produces previously unappreciated AHR-activating metabolites and promotes CRC cell proliferation via the AHR-TERT axis

Fusobacterium nucleatum (Fn) is prevalently enriched in colorectal cancer (CRC), promoting CRC progression. However, Fn-derived small molecules and their host target pathways in CRC remain largely underexplored. Here, we identify that Fn produces previously unrecognized three indole-containing metabolites, fusotrisindoline (FTIN), streptindole (STIN), and trisindoline (TIN). Using AHR reporter, CYP1A1 mRNA induction, CYP1A enzyme assay, photoaffinity AHR-ligand competition, and in silico docking, we establish that these metabolites are bona fide agonists of the aryl hydrocarbon receptor (AHR), with FTIN being the most potent AHR ligand (EC50 [~]41 nM in HepG2 cells). Genetic and pharmacological perturbations demonstrate that FTIN-activated AHR promotes proliferation, migration, and invasion in EGFR blockade-responsive CRC cell lines, such as SNU-C4, but not in EGFR blockade-resistant cell lines, such as HCT116. We show that FTIN-activated AHR signaling is critical for Fn-mediated promotion of CRC cell growth. A {Delta}tnaA mutant defective in indole production lacked FTIN/STIN/TIN production and was unable to activate AHR or enhance CRC cell growth in vitro and SNU-C4 xenograft growth in vivo. RNA-seq and follow-up functional validation identified TERT as a key downstream effector of FTIN-activated AHR signaling. FTIN upregulated TERT transcription and telomerase activity, and TERT knockdown abrogated FTIN-promoted CRC cell proliferation. FTIN production was conserved across Fn subspecies, as well as other Fusobacterium species, and detected in additional CRC- associated genera. In 30 patient pairs of CRC-matched normal colon tissues, FTIN was quantifiable in most CRC tissues and significantly enriched relative to matched normal colon tissues, whereas STIN/TIN were undetectable. Our findings reveal a metabolite-centered FTIN-AHR-TERT axis by which intratumoral bacteria, such as Fn, accelerate CRC growth and uncover FTIN as a potential biomarker in CRC.

microbiology↗

bioRxiv2025

A single extracellular vesicle-based platform supporting both RBD protein and mRNA vaccination against SARS-CoV-2

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syn-drome coronavirus 2 (SARS-CoV-2) has highlighted the need for novel, effective, and safe vaccine platforms. Extracellular vesicles (EVs) facilitate cell-to-cell communication and can modulate immune responses by delivering antigens. Here, we propose a versatile EV-based vaccine plat-form in which immune-stimulating EVs, engineered using acoustic shock waves (SW), are used to deliver either protein or mRNA antigens. Immunostimulatory EVs derived from LPS-activated THP-1 monocytes (aTEVs) were loaded with SARS-CoV-2 receptor-binding domain (RBD) protein or RBD-encoding mRNA via SW post-loading. Both aTEV-RBD-Pro and aTEV-RBD-mRNA elicited robust RBD-specific humoral and cellular immune responses in mice without the need for external adjuvants. Moreover, lyophilized aTEV-RBD-Pro vaccines retained immunogenicity after storage, supporting their chain-independent stability. These results demonstrate that a single EV-based platform can independently support both protein- and mRNA-based vaccination, highlighting its flexibility for next-generation vaccine development.

immunology↗

bioRxiv2025

γ-Amino Carboxylic Acid Modification Enhances the Efficacy of PNAs Targeting miR-221-3p in A549 Cells

Peptide nucleic acids (PNAs) are versatile tools for diagnostic and therapeutic applications, including gene regulation and miRNA targeting. However, their therapeutic potential is often limited by challenges such as biological efficacy. To address this, PNAs offer a key advantage over other nucleic acids--their ease of modification, which allows for enhanced properties. In this study, we introduced a novel{gamma} -amino carboxylic acid ({gamma}-ACA) modification to PNAs targeting miR-221-3p, a key miRNA implicated in various pathological processes. The modified PNAs showed significantly improved binding affinity to their targets and more efficient inhibition of miR-221-3p expression compared to unmodified PNAs in A549 cells, leading to effective regulation of downstream gene and protein expression. These results highlight the potential of{gamma} -modified PNAs as a platform for developing miRNA-targeted therapeutics.

molecular biology↗

bioRxiv2025

AI-Guided Discovery and Optimization of Antimicrobial Peptides Through Species-Aware Language Model

The rise of antibiotic-resistant bacteria drives an urgent need for novel antimicrobial agents. Antimicrobial peptides (AMPs) show promise solutions due to their multiple mechanisms of action and reduced propensity for resistance development. This study introduces LLAMP (Large Language model for AMP activity prediction), a target species-aware AI model that leverages pre-trained language models to predict minimum inhibitory concentration (MIC) values of AMPs. Analysis of attention values allowed us to pinpoint critical amino acid residues (e.g., Trp, Lys, and Phe). Our work demonstrates the potential of AI to expedite the discovery of peptide-based antibiotics to combat antibiotic resistance.

bioinformatics↗

bioRxiv2022

Temporal dynamics of the multi-omic response to endurance exercise training across tissues

Regular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues in Rattus norvegicus over 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex-specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of the Mef2 family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and are provided in an easily accessible public repository (https://motrpac-data.org/). HighlightsO_LIMulti-tissue resource identifies 35,439 analytes regulated by endurance exercise training at 5% FDR across 211 combinations of tissues and molecular platforms. C_LIO_LIInterpretation of systemic and tissue-specific molecular adaptations produced hypotheses to help describe the health benefits induced by exercise. C_LIO_LIRobust sex-specific responses to endurance exercise training are observed across multiple organs at the molecular level. C_LIO_LIDeep multi-omic profiling of six tissues defines regulatory signals for tissue adaptation to endurance exercise training. C_LIO_LIAll data are available in a public repository, and processed data, analysis results, and code to reproduce major analyses are additionally available in convenient R packages. C_LI

molecular biology↗

bioRxiv2021

Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates

Huntingtons disease is characterized by accumulation of the aggregation-prone mutant Huntingtin (mHTT) protein. Here, we show that expression of mHTT in mouse cultured cells activates IRE1, the transmembrane sensor of stress in the endoplasmic reticulum, leading to degradation of the Blos1 mRNA and repositioning of lysosomes and late endosomes toward the microtubule organizing center. Overriding Blos1 degradation results in excessive accumulation of mHTT aggregates in both cultured cells and primary neurons. Although mHTT is degraded by macroautophagy when highly expressed, we show that prior to the formation of large aggregates, mHTT is degraded via an ESCRT-dependent, macroautophagy-independent pathway consistent with endosomal microautophagy. This pathway is enhanced by Blos1 degradation and appears to protect cells from a toxic, less aggregated form of mHTT. Condensed titleBlos1 regulation protects from Huntingtin aggregation Short summaryHere the authors demonstrate that the regulation of Blos1 by the unfolded protein response prevents the excessive accumulation of Huntingtin, the protein that underlies Huntingtons disease. This pathway involves the macroautophagy-independent degradation of Huntingtin prior to its forming large aggregates.

cell biology↗