Biology subjects

Chen, S.

Publications and source records attributed to Chen, S..

At least 541 records · Page 30Linked to original sources

bioRxiv2023

GenBank genomics highlight the genomic features, genetic diversity and regulation of morphological, metabolic and disease-resistance traits in Nicotiana tabacum

Nicotiana tabacum is a model organism in plant molecular and pathogenic research and has significant potential in the production of biofuels and active pharmaceutical compounds in synthetic biology. Because of the large allotetraploid genome of tobacco, its genomic features, genetic diversity and genetic regulation of many complex traits remain unknown. In this study, we present a nearly complete chromosome-scale assembly of N. tabacum and provide evidence that homoeologous exchange between subgenomes and epigenetic remodelling are likely mechanisms of genome stabilization and subgenome coordination following polyploidization. By leveraging GenBank-scale sequencing and phenotyping data from 5196 lines, geography at the continent scale, rather than types assigned on the basis of curing crop practices, was found to be the most important correlate of genetic structure. Using 178 marker{square}trait associations detected in genome-wide association analysis, a reference genotype-to-phenotype map was built for 39 morphological, developmental, and disease-resistance traits. A novel gene, auxin response factor 9 (Arf9), associated with wider leaves after being knocked out, was fine-mapped to a single nucleotide polymorphism (SNP). This point mutation alters the translated amino acid from Ala203 to Pro203, likely preventing homodimer formation during DNA binding. Our analysis also revealed signatures of positive and polygenic selection for multiple traits during the process of selective breeding. Overall, this study demonstrated the power of leveraging GenBank genomics to gain insights into the genomic features, genetic diversity, and regulation of complex traits in N. tabacum, laying a foundation for future research on plant functional genomics, crop breeding, and the production of biopharmaceuticals and biofuels.

genetics↗

bioRxiv2023

Integrated analysis and annotation for T-cell receptor sequences using TCRosetta

BackgroundT cells and T cell receptors (TCRs) are essential components of the adaptive immune system. TCRs, on the surface of T cells, are responsible for recognizing and binding antigen peptide-MHC complex and play vital roles in T-cell immunology. Characterization of TCR repertoire offers a promising and high informative source for understanding the functions of T cells in immune responses and immunotherapies. Many researchers are now interested in TCR repertoire study; however, there are rare online servers for TCR analysis, especially no servers for TCR annotation and advanced analyses. ResultsWe developed TCRosetta, a comprehensive online server integrating the analytical methods for TCR repertoire/sequences analysis and visualization. TCRosetta combines general features analysis, large-scale sequence clustering, network construction, TCR-peptide binding prediction, generation probability calculation, and k-mer motif analysis for robust TCR sequence analysis, making TCR data analysis as simple as possible and allowing users to concentrate on research rather than coding. In addition, TCRosetta could annotate disease information for TRB CDR3 sequences by batch searching similar sequences in manually curated disease-related TCR database. The TCRosetta server accepts multiple input data formats and can analyze [~]20000 TCR sequences in less than three minutes. ConclusionsTCRosetta is the most comprehensive web server to date for TCR sequences/repertoires analysis and it is freely available at http://bioinfo.life.hust.edu.cn/TCRosetta/. It can be applied to help discover novel biomarkers for disease diagnosis and identify cancer-associated TCR sequences. WHAT IS ALERADY KNOWN ON THIS TOPICT cell receptor repertoires are largely untapped resource than can be used for predicting immune responses to different exposures including viral infections and tumor neoantigens. The downstream analysis of TCR repertoire is often performed by different tools requiring diverse operating environments and expertise. There is no webserver for comprehensive TCR repertoire analysis including general and advanced analysis. WHAT THIS STUDY ADDSWe developed TCRosetta, a comprehensive platform for analyzing T-cell repertoire which combines nearly all TCR analysis methods. It supports different kinds of the format of input including most mainstream TCR extraction tools or amino acid sequences. It could analyze the features of TCR repertoire and display them in interactive graphs and is the first platform with a batch search and TCR annotation function. HOW THIS STUDY MIGHT AFFECT RESEARCH, PACTICE OR POLICYTCRosetta can be applied to discover novel biomarkers to predict response in immunotherapy such TCR repertoire diversity and clonality. It also can identify cancer-associated TCR sequences by clustering biochemically similar CDR3 sequences. It can make TCR repertoire analysis as effortless as possible and help users focus on research instead of coding.

bioinformatics↗

bioRxiv2023

Optical tools for visualizing and controlling human GLP-1 receptor activation with high spatiotemporal resolution

The glucagon-like peptide-1 receptor (GLP1R) is a broadly expressed target of peptide hormones with essential roles in energy and glucose homeostasis, as well as of the blockbuster weight-loss drugs semaglutide and liraglutide. Despite its large clinical relevance, tools to investigate the precise activation dynamics of this receptor with high spatiotemporal resolution are limited. Here we introduce a novel genetically-encoded sensor based on the engineering of a circularly-permuted green fluorescent protein into the human GLP1R, named GLPLight1. We demonstrate that fluorescence signal from GLPLight1 accurately reports the expected receptor conformational activation in response to pharmacological ligands with high sensitivity (max {Delta}F/F0 = 528%) and temporal resolution ({tau}ON = 4.7 sec). We further demonstrated that GLPLight1 shows comparable responses to GLP-1 derivatives as observed for the native receptor. Using GLPLight1, we established an all-optical assay to characterize a novel photocaged GLP-1 derivative (photo-GLP1) and to demonstrate optical control of GLP1R activation. Thus, the new all-optical toolkit introduced here enhances our ability to study GLP1R activation with high spatiotemporal resolution.

biochemistry↗

bioRxiv2023

simCAS: an embedding-based method for simulating single-cell chromatin accessibility sequencing data

Single-cell chromatin accessibility sequencing (scCAS) technology provides an epigenomic perspective to characterize gene regulatory mechanisms at single-cell resolution. With an increasing number of computational methods proposed for analyzing scCAS data, a powerful simulation framework is desirable for evaluation and validation of these methods. However, existing simulators generate synthetic data by sampling reads from real data or mimicking existing cell states, which is inadequate to provide credible ground-truth labels for method evaluation. We present simCAS, an embedding-based simulator, for generating high-fidelity scCAS data from both cell-wise and peak-wise embeddings. We demonstrate simCAS outperforms existing simulators in resembling real data and show that simCAS can generate cells of different states with user-defined cell populations and differentiation trajectories. Additionally, simCAS can simulate data from different batches and encode user-specified interactions of chromatin regions in the synthetic data, which provides ground-truth labels more than cell states. We systematically demonstrate that simCAS facilitates the benchmarking of four core tasks in downstream analysis: cell clustering, trajectory inference, data integration, and cis-regulatory interaction inference. We anticipate simCAS will be a reliable and flexible simulator for evaluating the ongoing computational methods applied on scCAS data. AvailabilitysimCAS is freely available at https://github.com/Chen-Li-17/simCAS.

bioinformatics↗

bioRxiv2023

rtPA Directly Protects Neurons After Intracerebral Hemorrhage through PI3K/AKT/mTOR Pathway

Intracerebral hemorrhage (ICH) is an acute cerebrovascular disease with high disability and mortality rates. Recombinant tissue plasminogen activator (rtPA) is commonly applied for hematoma evacuation in minimally invasive surgery (MIS) after ICH. However, rtPA may contact directly with brain tissue during MIS procedure, which makes it necessary to discuss the safety of rtPA. We found that, in the in vivo ICH model induced by VII-type collagenase, rtPA treatment improved the neurological function of ICH mice, alleviated the pathological damage and decreased the apoptosis and autophagy level of the peri-hematoma tissue. In the in-vitro model of ICH induced by hemin, the administration of rtPA down-regulated neuronal apoptosis, autophagy, and endoplasmic reticulum stress of neurons. Transcriptome sequencing analysis showed that rtPA treatment upregulated the PI3K/AKT/mTOR pathway in neurons, and PI3K inhibitor (LY294002) can reverse the protective effects of rtPA in inhibiting excessive apoptosis, autophagy and ER-stress. Epidermal growth factor receptor inhibitor (AG-1487) reversed the effect of rtPA on PI3K/AKT/mTOR pathway, which might indicate that the EGF domain played an important role in the activation of PI3K/AKT/mTOR pathway.

neuroscience↗

bioRxiv2023

Cognitive relevance of an evolutionarily new and variable prefrontal structure

Identifying structure-function correspondences is a major goal among biologists, cognitive neuroscientists, and brain mappers. Recent studies have identified relationships between performance on cognitive tasks and the presence or absence of small, shallow indentations, or sulci, of the human brain. Building on the previous finding that the presence of one such sulcus in the left anterior lateral prefrontal cortex (aLPFC) was related to reasoning task performance in children and adolescents, we tested whether this relationship extended to a different sample, age group, and reasoning task. As predicted, the presence of this aLPFC sulcus--the ventral para-intermediate frontal sulcus--was also associated with higher reasoning scores in young adults (ages 22-36). These findings have not only direct developmental, but also evolutionary relevance--as recent work shows that the pimfs-v is exceedingly rare in chimpanzees. Thus, the pimfs-v is a novel developmental, cognitive, and evolutionarily relevant feature that should be considered in future studies examining how the complex relationships among multiscale anatomical and functional features of the brain give rise to abstract thought.

neuroscience↗

bioRxiv2023

RNPS1 stabilizes NAT10 protein to facilitate translation in cancer via tRNA ac4C modification

NAT10 is dysregulated and plays an essential role in various types of cancers. However, the exact machenism of how NAT10 regulates cancer progression remains debatable. In this report, we show that NAT10 affects tumorigeneis mainly based on its acetylation function on tRNA. In addition, we found NAT10 regulate the ac4C of tRNA in cancer via interaction with RNPS1, which in turn protect NAT10 from degradation by E3 ubiquitin ligase ZSWIM6. We developed TRMC-seq method to compreshensively profile tRNA ac4C sites and uncovered the presence of ac4C in a broader range of tRNA isoacceptors than previous studies. Multi-omics analysis identified AP-1 signaling pathway as a major downstream mediator of NAT10. Mechanistically, we found NAT10 is responsible for the translation efficiency genes which contain higher ac4C-tRNA codon. Importantly, our genetic mouse model validated our in vitro findings of NAT10 in cancer. Our study highlights a role of NAT10 in mediating tRNA ac4C to regulate the translation and tumorigenesis of cancer.

molecular biology↗

bioRxiv2023

ABI5-FLZ13 Module Transcriptionally Represses Growth-related Genes to Delay Seed Germination in Response to ABA

The bZIP transcription factor ABSCISIC ACID INSENSITIVE5 (ABI5) is a master regulator determining seed germination and postgerminative growth in response to abscisic acid (ABA), but the detailed molecular mechanism underlying the repression function of ABI5 in plant growth remains to be characterized. In this study, we used proximity labeling (PL) to map the neighboring proteome of ABI5 and identified FCS-LIKE ZINC FINGER PROTEIN 13 (FLZ13) as an up-to-now unknown ABI5-interacting partner. Phenotypic analysis of flz13 mutants and FLZ13-overexpressing lines demonstrated that FLZ13 acts as a positive regulator of ABA signaling. Interestingly, transcriptomic analysis showed that ABI5 and FLZ13 co-downregulate the expression of ABA-repressed and growth-related genes involved in chlorophyll biosynthesis, photosynthesis and cell wall organization, thereby repressing seed germination and seedling establishment in response to ABA. Further genetic analysis proved that FLZ13 works synergistically with ABI5 to regulate seed germination. Collectively, our study reveals a previously uncharacterized transcriptional regulatory mechanism regarding ABA-inhibited seed germination and seedling establishment.

plant biology↗

bioRxiv2023

Image-guided deployment and monitoring of a novel tungsten nanoparticle-infused radiopaque absorbable inferior vena cava filter in pig

The use of absorbable inferior vena cava filters (IVCFs) constructed with poly-p-dioxanone (PPDO) eliminates risks and complications associated with the use of retrievable metallic filters. Radiopacity of radiolucent PPDO IVCFs can be improved with the incorporation of nanoparticles (NPs) made of high-atomic number materials such as gold and bismuth. In this study, we focused on incorporating tungsten NPs (WNPs), along with polyhydroxybutyrate (PHB), polycaprolactone (PCL), and polyvinylpyrrolidone (PVP) polymers to increase the surface adsorption of the WNPs. We compared the imaging properties of WNPs with single-polymer PHB (W-P) and WNPs with polymer blends consisting of PHB, PCL, and PVP (W-PB). Our in vitro analyses using PPDO sutures showed enhanced radiopacity with either W-P or W-PB coating, without compromising the inherent physico-mechanical properties of the PPDO sutures. We observed a more sustained release of WNPs from W-PB-coated sutures than W-P-coated sutures. We successfully deployed W-P- and W-PB-coated IVCFs into the inferior vena cava of pig models, with monitoring by fluoroscopy. At the time of deployment, W-PB-coated IVCFs showed a 2-fold increase in radiopacity compared to W-P-coated IVCFs. Longitudinal monitoring of in vivo IVCFs over a 12-week period showed a drastic decrease in radiopacity at week 3 for both filters. Results of this study highlight the utility of NPs and polymers for enhancing radiopacity of medical devices; however, different methods of incorporating NPs and polymers can still be explored to improve the efficacy, safety, and quality of absorbable IVCFs.

bioengineering↗

bioRxiv2023

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms

Homeodomain transcription factors (HD TFs) are instrumental to vertebrate development. Mutations in HD TFs have been linked to human diseases, but their pathogenic mechanisms remain elusive. Here we use Cone-Rod Homeobox (CRX) as a model to decipher the disease-causing mechanisms of two HD mutations, p.E80A and p.K88N, that produce severe dominant retinopathies. Through integrated analysis of molecular and functional evidence in vitro and in knock-in mouse models, we uncover two novel gain-of-function mechanisms: p.E80A increases CRX-mediated transactivation of canonical CRX target genes in developing photoreceptors; p.K88N alters CRX DNA-binding specificity resulting in binding at ectopic sites and severe perturbation of CRX target gene expression. Both mechanisms produce novel retinal morphological defects and hinder photoreceptor maturation distinct from loss-of-function models. This study reveals the distinct roles of E80 and K88 residues in CRX HD regulatory functions and emphasizes the importance of transcriptional precision in normal development.

genetics↗

bioRxiv2023

Identification and characterization of a proliferative cell population in estrogen receptor-positive metastatic breast cancer through spatial and single-cell transcriptomics

BackgroundIntratumor heterogeneity is a hallmark of most solid tumors, including breast cancers. We applied spatial transcriptomics and single-cell RNA-sequencing technologies to profile spatially resolved cell populations within estrogen receptor-positive (ER+) metastatic breast cancers and elucidate their importance in estrogen-dependent tumor growth. MethodsSpatial transcriptomics and single-cell RNA-sequencing were performed on two patient-derived xenografts (PDXs) of "ER-high" metastatic breast cancers with opposite estrogen-mediated growth responses: estrogen-suppressed GS3 (80-100% ER) and estrogen-stimulated SC31 (30-75% ER) models. The analyses included samples treated with and without 17{beta}-estradiol. The findings were validated via scRNA-seq analyses on "ER-low" estrogen-accelerating PDX, GS1 (5% ER). The results from our spatial and single-cell analyses were further supported by the analysis of a publicly available single cell dataset and a protein-based dual immunohistochemical (IHC) evaluation using three important clinical markers [i.e., ER, progesterone receptor (PR), and Ki67]. The translational implication of these results was assessed by clinical outcome analyses on public breast cancer cohorts. ResultsOur novel space-gene-function study revealed a "proliferative" cell population in addition to three major spatially distinct compartments within ER+ metastatic breast cancers. These compartments showed functional diversity (i.e., estrogen-responsive, proliferative, hypoxia-induced, and inflammation-related). The "proliferative (MKI67+)" population, not "estrogen-responsive" compartment, was crucial for estrogen-dependent tumor growth, leading to the acquisition of luminal B features. The cells with induction of typical estrogen-responsive genes such as PGR were not directly linked to estrogen-dependent proliferation. Additionally, the dual IHC analyses demonstrated the distinct contribution of the Ki67+ proliferative cells toward estrogen-mediated growth and their response to palbociclib, a CDK4/6 inhibitor. The gene signatures developed from the proliferative, hypoxia-induced, and inflammation-related compartments were significantly correlated with worse clinical outcomes, while patients with the high estrogen-responsive scores showed better prognosis, confirming that the estrogen-responsive compartment would not be directly associated with estrogen-dependent tumor progression. ConclusionsFor the first time, our study elucidated a "proliferative" cell population distinctly distributed in ER+ metastatic breast cancers. They contribute differently toward progression of these cancers, and the gene signature in the "proliferative" compartment is an important determinant of luminal cancer subtypes.

cancer biology↗

bioRxiv2023

Depletion-assisted multiplexing cell-free RNA sequencing reveals distinct human and microbial signatures in plasma versus extracellular vesicle

Cell-free long RNAs in human plasma and extracellular vesicles (EVs) have shown promise as biomarkers in liquid biopsy, despite their fragmented nature. To investigate these fragmented cell-free RNAs (cfRNAs), we developed a cost-effective cfRNA sequencing method called DETECTOR-seq (depletion-assisted multiplexed cell-free total RNA sequencing). DETECTOR-seq utilized a meticulously tailored set of customized guide RNAs to remove large amounts of unwanted RNAs (i.e., fragmented ribosomal and mitochondrial RNAs) in human plasma. Early barcoding strategy was implemented to reduce costs and minimize plasma requirements. Using DETECTOR-seq, we conducted a comprehensive analysis of cell-free transcriptomes in both whole human plasma and EVs. Our analysis revealed discernible distributions of RNA types in plasma and EVs. Plasma exhibited pronounced enrichment in structured circular RNAs, tRNAs, Y RNAs, and viral RNAs, while EVs showed enrichment in mRNAs and srpRNAs. Functional pathway analysis highlighted RNA splicing-related ribonucleoproteins (RNPs) and antimicrobial humoral response genes in plasma, while EVs demonstrated enrichment in transcriptional activity, cell migration, and antigen receptor-mediated immune signals. Our study indicates the comparable potential of cfRNAs from whole plasma and EVs in distinguishing cancer patients (i.e., colorectal and lung cancer) from healthy donors. And microbial cfRNAs in plasma showed potential in classifying specific cancer types. Our comprehensive analysis of total and EV cfRNAs in paired plasma samples provides valuable insights for determining the need for EV purification in cfRNA-based studies. We envision the cost-effectiveness and efficiency of DETECTOR-seq will empower transcriptome-wide investigations in the fields of extracellular vesicles and liquid biopsy.

molecular biology↗

bioRxiv2023

Cell-free multi-omics analysis reveals tumor status-informative signatures in gastrointestinal cancer patients' plasma

During cancer development, hosts tumorigenesis and immune signals are released to and informed by circulating molecules, like cell-free DNA (cfDNA) and RNA (cfRNA) in blood. However, these two kinds of molecules are still not systematically compared in gastrointestinal cancer. Here, we profiled 4 types of cell-free omics data from colorectal and stomach cancer patients, and assayed 15 types of genomic, epi-genomic, and transcriptomic variations. First, we demonstrated that the multi-omics data were more capable of detecting cancer genes than the single-omics data, where cfRNAs were more sensitive and informative than cfDNAs in terms of detection ratio, variation type, altered number, and enriched functional pathway. Moreover, we revealed several peripheral immune signatures that were suppressed in cancer patients and originated from specific circulating and tumor-microenvironment cells. Particularly, we defined a {gamma}{delta}-T-cell score and a cancer-associated-fibroblast (CAF) score using the cfRNA-seq data of 143 cancer patients. They were informative of clinical status like cancer stage, tumor size, and survival. In summary, our work reveals the cell-free multi-molecular landscape of colorectal and stomach cancer, and provides a potential monitoring utility in blood for the personalized cancer treatment.

systems biology↗

bioRxiv2023

Normative Modeling of Brain Morphometry Across the Lifespan using CentileBrain: Algorithm Benchmarking and Model Optimization

We present an empirically benchmarked framework for sex-specific normative modeling of brain morphometry that can inform about the biological and behavioral significance of deviations from typical age-related neuroanatomical changes and support future study designs. This framework was developed using regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The Multivariate Factorial Polynomial Regression (MFPR) emerged as the preferred algorithm optimized using nonlinear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins, and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3,000 study participants. The model and scripts described here are freely available through CentileBrain (https://centilebrain.org/).

bioinformatics↗

bioRxiv2023

Phenotypically Complex Living Materials Containing Engineered Cyanobacteria

A cyanobacterial photosynthetic biocomposite material was fabricated using 3D-printing and bioengineered to produce multiple functional outputs in response to an external chemical stimulus. Our investigations show the advantages of utilizing additive manufacturing techniques in controlling the design and shape of the fabricated materials, which proved to be important for the support and growth of obligate phototrophic microorganisms within the material. As an initial proof-of-concept, a synthetic theophylline-responsive riboswitch in Synechococcus elongatus PCC 7942 was used for regulating the expression of a yellow fluorescent protein (YFP) reporter. Upon induction with theophylline, the encapsulated cells produced YFP within the hydrogel matrix. Subsequently, a strain of S. elongatus was engineered to produce an oxidative enzyme that is useful for bioremediation, laccase, expressed either constitutively or under the control of the riboswitch. The responsive biomaterial can decolorize a common textile dye pollutant, indigo carmine, potentially serving as a useful tool in environmental bioremediation. Finally, cells were engineered to have the capacity for inducible cell death to eliminate their presence once their activity is no longer required, which is an important function for biocontainment and minimizing unintended environmental impact. By integrating genetically engineered stimuli-responsive cyanobacteria in patterned volumetric 3D-printed designs, we demonstrate the potential of programmable photosynthetic biocomposite materials capable of producing functional outputs including, but not limited to, bioremediation.

bioengineering↗

bioRxiv2023

Active Gαi/o mutants accelerate breast tumor metastasis via the c-Src pathway

Constitutively active mutations in the Gi2 and GoA subunits of heterotrimeric G proteins have been identified in several human cancers including breast cancer, but their functional significance in tumorigenesis and metastasis has not been well characterized. In this study, we show that expression of the constitutively active GoAR243H and Gi2R179C mutants alone was insufficient to induce mammary tumor formation in mice. However, in transgenic mouse models of breast cancer induced by Neu expression or PTEN loss, we found that the Gi2R179C mutant enhanced spontaneous lung metastasis while having no effect on primary tumor initiation and growth. Additionally, we observed that ectopic expression of the GoAR243H and Gi2R179C mutants in tumor cells promote cell migration in vitro as well as dissemination into multiple organs in vivo by activating c-Src signaling. Thus, our study uncovers a critical function of Gi/o signaling in accelerating breast cancer metastasis via the c-Src pathway. This work is clinically significant, as it can potentially pave the way to personalized therapies for patients who present with active Gi/o mutations or elevated Gi/o signaling by targeting c-Src to inhibit breast cancer metastasis.

cancer biology↗

bioRxiv2023

Exposure to high-sugar diet induces transgenerational changes in sweet sensitivity and feeding behavior via H3K27me3 reprogramming

Human health is facing a host of new threats linked to unbalanced diets, including high sugar diet (HSD), which contributes to the development of both metabolic and behavioral disorders. Studies have shown that diet-induced metabolic dysfunctions can transmit to multiple generations of offspring and exert long-lasting health burden. Meanwhile, whether and how diet-induced behavioral abnormalities can be transmitted to the offspring remain largely unclear. Here, we showed that ancestral HSD exposure suppressed sweet sensitivity and feeding behavior in the offspring in Drosophila. These behavioral deficits were transmitted through the maternal germline and companied by the enhancement of H3K27me3 modifications. PCL-PRC2 complex, a major driver of H3K27 trimethylation, was upregulated by ancestral HSD exposure, and disrupting its activity eliminated the transgenerational inheritance of sweet sensitivity and feeding behavior deficits. Elevated H3K27me3 inhibited the expression of a transcriptional factor Cad and suppressed sweet sensitivity of the sweet-sensing gustatory neurons, reshaping the sweet perception and feeding behavior of the offspring. Taken together, we uncovered a novel molecular mechanism underlying behavioral abnormalities across multiple generations of offspring upon ancestral HSD exposure, which would contribute to the further understanding of long-term health risk of unbalanced diet.

neuroscience↗

bioRxiv2023

Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to Serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploring Sarbecovirus evolution. Author SummaryThe Spike strain of SARS-CoV-2 has accumulated many mutations during its time in circulation, most of which have occurred in the S1 region, and more specifically in the RBD, in an effort to either improve the viruss affinity for the receptor ACE2 or to enhance its ability to evade the immune system. Mutations in the Spike S2 region have more far-reaching effects than those in the S1 region because it is more conserved across sarbecoviruses. By comparing SARS and SARS2, we found that an important substitution at amino acid position 813 in the S2 region (T813S) disrupts the utilization of TMPRSS2 and can significantly influence viral entry into cells. This discovery deepens our knowledge of S proteins and provides new prospects for tracing the evolution of Sarbecoviruses.

microbiology↗