Biomedical subjects

Ying Wu

Publications and source records attributed to Ying Wu.

5 recordsLinked to original sources

PubMed2026

Noncanonical bactericidal activity of teleost type I interferon is conferred by a membrane-targeting C-terminal peptide.

Type I interferons (IFNs) are indispensable antiviral cytokines in nonspecific immunity, yet they play dual roles in bacterial infections in mammals. Recent studies have revealed a subset of strongly cationic type I IFNs possessing potent antimicrobial properties across nonmammalian vertebrates. In this study, we identified a type I IFN gene, CaIFNi, from Cromileptes altivelis that is characterized by a unique triple-disulfide bond architecture. In Vibrio harveyi-challenged models, overexpression of CaIFNi potentiated bacterial clearance capacity in tissues, whereas its knockdown exacerbated bacterial colonization, highlighting its ability to protect the host against bacterial infection in vivo. In vitro assays further confirmed that CaIFNi directly binds to and kills both gram-negative (G-) and gram-positive (G+) bacteria, which first revealed the antibacterial function of new subgroup IFNi within teleost type I IFNs. Furthermore, the α-helical peptide CaIFNi-18 derived from CaIFNi was identified as a novel antimicrobial peptide (AMP) that has broad-spectrum antibacterial efficacy against G- and G+ bacteria and membrane-targeting ability. Further mechanistic studies revealed that CaIFNi has bactericidal effects on both G- and G+ bacteria through membrane depolarization and disruption, alteration of the bacterial ultrastructure, and in vitro binding to genomic DNA. In addition, CaIFNi-18 also has significant in vivo therapeutic efficacy against bacterial infection, highlighting its great potential as an antibacterial agent. Encouragingly, the loss of antibacterial activity in the truncation mutant (rCaIFNiΔ148-165) lacking the CaIFNi-18 segment suggests that this region is essential for the bactericidal function of the full-length protein and likely acts as its core domain. Further computational simulations revealed that the deletion of the CaIFNi-18 region attenuated the interaction between the protein and the bacterial membrane. These findings not only expand the functional scope of type I IFNs beyond their canonical antiviral role but also identify their derivative CaIFNi-18 as both a promising antimicrobial candidate and the essential bactericidal domain of CaIFNi, thereby offering novel therapeutic strategies against bacterial infections in the aquaculture industry and beyond.

Animals↗

PubMed2026

Skin-innervating glutamatergic neurons modulate aging.

Peripheral nerves regulate skin homeostasis by secreting neurotransmitters, but their role during skin aging remains incompletely understood. Here, we report that cutaneous denervation accelerates skin aging, as evidenced by collagen reduction. Neurofilament heavy chain (Nefh) is decreased in aged skin and is predominantly expressed in vesicular glutamate transporter 2-positive (Vglut2+) skin-innervating glutamatergic neurons. Notably, dermal fibroblasts, the primary producers of collagen, frequently contact Nefh+ nerve fibers. Moreover, Nefh deletion in Vglut2+ glutamatergic neurons drives skin fibroblast senescence and collagen loss, whereas additional glutamate improves skin aging phenotypes. Mechanistically, cyclin-dependent kinase 5 (Cdk5) interacts with both Nefh and Vglut2 and maintains glutamate release and collagen homeostasis. Additionally, in skin fibroblasts, solute carrier family 1 member 3 (Slc1a3) governs the collagen-promoting and anti-senescence functions of glutamate. Together, these findings reveal Nefh-mediated glutamatergic neuromodulation of skin aging and provide therapeutic targets for aging-related skin disorders.

Animals↗

PubMed2026

NOTCH3 Internal Tandem Duplication Defines a Novel Oncogenic Activation Mechanism of NOTCH Signaling.

NOTCH signaling is activated in tumors through multiple mechanisms, including mutations, gene rearrangements, and gene amplification. We report a novel activation mechanism, an internal tandem duplication (ITD) near the NOTCH3 negative regulatory region (NRR), found in a myogenic mesenchymal neoplasm. This 17-amino acid residue duplication disrupts the tightly autoinhibited structure surrounding the S2 cleavage site, resulting in ligand-independent S2 cleavage and constitutive pathway activation, as demonstrated by increased expression of the NOTCH3 target gene HES1. Cells expressing NOTCH3-ITD showed increased nuclear localization of the receptor and exhibited malignant phenotypes, including enhanced proliferation and migration. Together, these findings support the oncogenic role of NOTCH3-ITD.

Receptor, Notch3↗

PubMed2025

Long-read sequencing of single cell-derived melanoma subclones reveals divergent and parallel genomic and epigenomic evolutionary trajectories.

Tumor evolution is driven by various mutational processes, ranging from single-nucleotide variants (SNVs) to large structural variants (SVs) to dynamic shifts in DNA methylation. Current short-read sequencing methods struggle to accurately capture the full spectrum of these genomic and epigenomic alterations due to inherent technical limitations. To overcome that, here we introduce an approach for long-read sequencing of single-cell derived subclones, and use it to profile 23 subclones of a mouse melanoma cell line, characterized with distinct growth phenotypes and treatment responses. We develop a computational framework for harmonization and joint analysis of different variant types in the evolutionary context. Uniquely, our framework enables detection of recurrent amplifications of putative driver genes, generated by independent SVs across different lineages, suggesting parallel evolution. In addition, our approach revealed gradual and lineage-specific methylation changes associated with aggressive clonal phenotypes. We also show our set of phylogeny-constrained variant calls along with openly released sequencing data can be a valuable resource for the development of new computational methods.

Journal Article↗

PubMed2024

Super Enhanced Purification of Denatured-Refolded Ubiquitinated Proteins by ThUBD Revealed Ubiquitinome Dysfunction in Liver Fibrosis.

Ubiquitination is crucial for maintaining protein homeostasis and plays a vital role in diverse biological processes. Ubiquitinome profiling and quantification are of great scientific significance. Artificial ubiquitin-binding domains (UBDs) have been widely employed to capture ubiquitinated proteins. The success of this enrichment relies on recognizing native spatial structures of ubiquitin and ubiquitin chains by UBDs under native conditions. However, the use of native lysis conditions presents significant challenges, including insufficient protein extraction, heightened activity of deubiquitinating enzymes and proteasomes in removing the ubiquitin signal, and purification of a substantial number of contaminant proteins, all of which undermine the robustness and reproducibility of ubiquitinomics. In this study, we introduced a novel approach that combines denatured-refolded ubiquitinated sample preparation (DRUSP) with a tandem hybrid UBD for ubiquitinomic analysis. The samples were effectively extracted using strongly denatured buffers and subsequently refolded using filters. DRUSP yielded a significantly stronger ubiquitin signal, nearly three times greater than that of the Control method. Then, eight types of ubiquitin chains were quickly and accurately restored; therefore, they were recognized and enriched by tandem hybrid UBD with high efficiency and no biases. Compared with the Control method, DRUSP showed extremely high efficiency in enriching ubiquitinated proteins, improving overall ubiquitin signal enrichment by approximately 10-fold. Moreover, when combined with ubiquitin chain-specific UBDs, DRUSP had also been proven to be a versatile approach. This new method significantly enhanced the stability and reproducibility of ubiquitinomics research. Finally, DRUSP was successfully applied to deep ubiquitinome profiling of early mouse liver fibrosis with increased accuracy, revealing novel insights for liver fibrosis research.

Animals↗