Biology subjects

Zhang, Y.-W.

Publications and source records attributed to Zhang, Y.-W..

8 recordsLinked to original sources

bioRxiv2026

High glucose confers senescence resistance via GLUT1 epigenetic rewiring to blunt immunotherapy responses in esophageal squamous cell carcinoma

Therapeutic resistance and undefined predictive biomarkers severely hinder the clinical popularization of immunotherapy in esophageal squamous cell carcinoma (ESCC). Herein, we identify the glucose transporter 1 (GLUT1) as a critical determinant of immunotherapy resistance. Elevated expression of GLUT1 correlates with poor immunotherapy response and unfavorable prognosis in ESCC patients. GLUT1 deletion or inhibition enhances CD8 T cell infiltration and cytotoxicity, and sensitizes ESCC tumors to anti-PD-1 (-PD1) therapy. Importantly, dietary glucose restriction exhibits equivalent antitumor efficacy to GLUT1 inhibition when combined with -PD1. Mechanistically, GLUT1 establishes a positive feedback loop with HAT1 and FOXM1, which epigenetically remodels chromatin accessibility to suppress tumor cell senescence, thereby impeding CD8 T cell-mediated antitumor immunity. Our findings highlight GLUT1 as a predictive biomarker of immunotherapy resistance and suggest dietary glucose restriction as a viable strategy to potentiate immunotherapy efficacy in ESCC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/738372v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@c2c5d5org.highwire.dtl.DTLVardef@14a34c7org.highwire.dtl.DTLVardef@cf05e4org.highwire.dtl.DTLVardef@18bc354_HPS_FORMAT_FIGEXP M_FIG C_FIG SHORT SUMMARYDong et al. identify glucose transporter 1 (GLUT1) as a predictor of poor response to immunotherapy in esophageal squamous cell carcinoma. GLUT1 promotes immune evasion by forming a positive feedback loop with the HAT1/FOXM1 anti-senescence axis, thereby epigenetically remodeling chromatin accessibility. GLUT1 inhibition or dietary glucose restriction restores CD8 T-cell-mediated antitumor immunity and improves the efficacy of anti-PD-1 therapy in preclinical models.

cancer biology↗

bioRxiv2026

A proteostasis clock underlies the timing of bacterial dormancy and antibiotic tolerance

Bacterial dormancy is a major contributor to antibiotic tolerance and persistent infection, yet the lag time before growth resumption is commonly viewed as a passive consequence of cellular recovery and remains difficult to manipulate. Protein aggregation has been linked to bacterial dormancy, but whether aggregates merely reflect cellular damage or directly regulate lag time remains unclear. Here we show that lag time is quantitatively set by cellular proteostasis through control of replication initiation. Microscopy and proteomic analyses revealed delayed aggregate disassembly as a shared proteostasis defect of long-lag bacteria. We identified the replication initiator DnaA in aggregates, whose spatial separation from the nucleoid directly suppresses DNA synthesis. Combined in vitro reconstitution revealed that aggregation-prone proteins drive dose-dependent, synergistic co-aggregation of DnaA, coupling aggregate burden to DnaA sequestration and lag-time extension. Across diverse genetic and physiological models, we observed a universal scaling relationship between lag-time extension and proteostasis decline. Genetic and chemical perturbations of this proteostasis-replication axis bidirectionally modulate lag time, with increasing proteostasis burden prolonging dormancy and restoring proteostasis or DnaA availability accelerating awakening. We therefore propose that proteostasis functions as a tunable timekeeping system for bacterial dormancy by regulating replication initiation, providing a basis for manipulating bacterial dormancy and antibiotic tolerance.

microbiology↗

bioRxiv2025

LadybirdBase: a comprehensive biology, ecology and omics resource for ladybird beetles (Coccinellidae)

Ladybird beetles (Coleoptera: Coccinellidae) represent a highly diverse insect group comprising over 6000 species. Recently, an increasing amount of omics data on ladybirds has accumulated. To better understand their roles and adaptations in biological control, we developed LadybirdBase (http://www.ladybirdbase.com/), a comprehensive database that compiles both published and self-collected data on ladybird beetles. It contains five main modules that encompass: (1) the Biology Module summarizing information on over 6000 species, including their classification, morphology, diet, distribution, and omics data; (2) the Ecology Module offering diet and distribution records; (3) the Genomics Module integrating published and unpublished resources such as genomes, transcriptomes, mitogenomes, orthogroups, and variance; (4) the Microbiomics Module presenting 16S rRNA, ITS, and metagenome data; and (5) the Lab Test Module covering diet ranges, life histories under different treatments, and stress tolerance. Additionally, LadybirdBase offers analysis tools for species detection using morphology or barcodes, BLAST searches against the genome resources, differential gene expression analysis, and PCR primer search. LadybirdBase can greatly simplify species identification, enhance the efficiency of omics studies, and provide a theoretical foundation for the use of ladybirds in biological control.

bioinformatics↗

bioRxiv2025

The Role of Chloride Ions in Serotonin Transport

The human serotonin (5-HT+) transporter SERT facilitates 5-HT+ transport into cells by coupling it to Na+ symport and K+ antiport. Although extracellular Cl- is also essential for transport, Cl-co-transport has been disputed, raising questions about the role of Cl- ions and why they are required. We show that Cl- gradients do not impact 5-HT+ accumulation, indicating that Cl- does not provide a driving force for uptake and arguing against stoichiometric Cl- symport. The presence of Cl- had only a small effect on Na+-mediated cytoplasmic pathway closure but markedly reduced the accessibility of residues in the extracellular pathway, consistent with modulation of the outward-facing states. Simulations illustrate that Cl- interacts strongly with a bound Na+ ion and stabilizes helix packing on the extracellular side. We propose that Cl- acts as an essential architectural cofactor by enhancing Na+ affinity and interactions between helices, thereby facilitating transport-related conformational transitions. Significance statementThe serotonin transporter (SERT) clears serotonin from synapses and is the target of widely used antidepressants. Although chloride ions are known to be required for SERT function, whether chloride is transported together with serotonin has remained unresolved for decades. We show that chloride gradients do not drive serotonin uptake, arguing against chloride symport. Instead, chloride stabilizes specific conformations of the transporter by strengthening sodium binding and extracellular helix packing. These findings redefine chloride not as a transported substrate, but as an architectural cofactor that facilitates conformational transitions required for transport. This reinterpretation reshapes our understanding of ion dependence in SERT and suggests a broader principle: ion requirements in related transporters may reflect structural stabilization rather than obligatory symport.

biochemistry↗

bioRxiv2023

Identification of the potassium binding site in serotonin transporter SERT

Clearance of serotonin (5-hydroxytryptamine, 5-HT) from the synaptic cleft after neuronal signaling is mediated by serotonin transporter SERT, which couples this process to the movement of a Na+ ion down its chemical gradient. After release of 5-HT and Na+ into the cytoplasm, the transporter faces a rate-limiting challenge of resetting its conformation to be primed again for 5-HT and Na+ binding. Early studies of vesicles containing native SERT revealed that K+ gradients can provide an additional driving force, via K+ antiport. Moreover, under appropriate conditions, a H+ ion can replace K+. Intracellular K+ accelerates the resetting step. Structural studies of SERT have identified two binding sites for Na+ ions, but the K+ site remains enigmatic. Here, we show that K+ antiport can drive substrate accumulation into vesicles containing SERT extracted from a heterologous expression system, allowing us to study the residues responsible for K+ binding. To identify candidate binding residues, we examine many cation binding configurations using molecular dynamics simulations, predicting that K+ binds to the so- called Na2 site. Site directed mutagenesis of residues in this site can eliminate the ability of both K+ and H+ to drive 5-HT accumulation into vesicles and, in patch clamp recordings, prevent the acceleration of turnover rates and the formation of a channel-like state by K+ or H+. In conclusion, the Na2 site plays a pivotal role in orchestrating the sequential binding of Na+ and then K+ (or H+) ions to facilitate 5-HT uptake in SERT. Significance statementNeuronal signaling depends on efficient clearance of the neurotransmitter from the synaptic cleft. To this end, proteins such as serotonin transporter (SERT) leverage the gradients of Na+ and K+ ions across the cell membrane, generated by Na+/K+-ATPase. While the role of Na+ in neurotransmitter transport is well understood, our understanding of the role of potassium in SERT has been limited. In this study, the authors use a combination of biochemical, electrophysiological, and computational tools, to identify the Na2 site as the binding site for K+, shedding light on a critical aspect of neurotransmitter transport.

biochemistry↗

bioRxiv2020

Chloride-dependent conformational changes in the GlyT1 glycine transporter

The human GlyT1 glycine transporter requires chloride for its function. However, the mechanism by which Cl- exerts its influence is unknown. To examine the role that Cl- plays in the transport cycle, we measured the effect of Cl- on both glycine binding and conformational changes. The ability of glycine to displace the high-affinity radioligand [3H]CHIBA-3007 required Na+ and was potentiated over 1000-fold by Cl-. We generated GlyT1b mutants containing reactive cysteine residues in either the extracellular or cytoplasmic permeation pathways and measured changes in the reactivity of those cysteine residues as indicators of conformational changes in response to ions and substrate. Na+ increased accessibility in the extracellular pathway and decreased it in the cytoplasmic pathway, consistent with stabilizing an outward-open conformation as observed in other members of this transporter family. In the presence of Na+, both glycine and Cl- independently shifted the conformation of GlyT1b toward an outward-closed conformation. Together, Na+, glycine and Cl- stabilized an inward-open conformation of GlyT1b. We then examined whether Cl- acts by interacting with a conserved glutamine to allow formation of an ion pair that stabilizes the closed state of the extracellular pathway. Molecular dynamics simulations of a GlyT1 homologue indicated that this ion pair is formed more frequently as that pathway closes. Mutation of the glutamine blocked the effect of Cl-, and substituting it with glutamate or lysine resulted in outward- or inward-facing transporter conformations, respectively. These results provide novel and unexpected insight into the role of Cl- in this family of transporters.

biochemistry↗

bioRxiv2020

mrMLM v4.0: An R Platform for Multi-locus Genome-wide Association Studies

Previous studies reported that some important loci are missed in single-locus genome-wide association studies (GWAS), especially because of the large phenotypic error in field experiments. To solve this issue, multi-locus GWAS methods have been recommended. However, only a few software packages are available. Therefore, an R software mrMLM, which includes our six multi-locus methods, was developed. mrMLM includes three components: dataset input, parameter setting and result output. The fread function in data.table is used to quickly read datasets, especially big datasets, and the doParallel package is used to conduct parallel computation using multiple CPUs. In addition, the graphical user interface software mrMLM.GUI v4.0, built upon Shiny, is also available. To confirm the correctness of the above programs, the same simulation datasets as used in previous studies, along with three real datasets, were re-analyzed by all the methods in mrMLM v4.0 and three widely-used methods. The results confirmed the advantages of our multi-locus methods over the current methods. The conclusion is also consistent with those in a Research Topic in Frontiers in Plant Science. Although a less stringent significance threshold is adopted, the false positive rates are effectively controlled. mrMLM is publicly available at https://cran.r-project.org/web/packages/mrMLM/index.html or https://bigd.big.ac.cn/biocode/tools/BT007077 as an open-source software.

genetics↗

bioRxiv2018

Structural elements required for coupling ion and substrate transport in the neurotransmitter transporter homolog LeuT.

The coupled transport of ions and substrates allows transporters to accumulate substrates using the energy in transmembrane ion gradients and electrical potentials. During transport, conformational changes that switch accessibility of substrate and ion binding sites from one side of the membrane to the other must be controlled so as to prevent uncoupled movement of ions or substrates. In the Neurotransmitter:Sodium Symporter (NSS) family, Na+ stabilizes the transporter in an outward-open state, thus decreasing the likelihood of uncoupled Na+ transport. In a step essential for coupled transport, substrate binding must overcome the effect of Na+, allowing intracellular substrate and Na+ release from an inward-open state. However, it is unclear which specific elements of the protein mediate this conformational response to substrate binding. Previously, we showed that in the prokaryotic NSS transporter LeuT, the effect of Na+ on conformation occurs at the Na2 site, where it influences conformation by fostering interaction between two domains of the protein (JBC 291: 1456, 2016). Here, we identify a conserved tyrosine residue in the substrate binding site required for substrate to enable conversion to inward-open states by establishing an interaction between the two transporter domains. We further identify additional interactions between the two transporter domains in the extracellular pathway that are required. Together with our previous work on the conformational effect of Na+, these results identify mechanistic components underlying ion-substrate coupling in NSS transporters.

biochemistry↗