Biology subjects

Sun, C.

Publications and source records attributed to Sun, C..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Origin and rapid evolution of minicircular and highly heteroplasmic mitogenome in the holoparasitic plant genus Rhopalocnemis

The holoparasitic plant Rhopalocnemis phalloides displays unique features in mitogenome organization, sequence heteroplasmy, DNA replication and gene transcription. To understand the origin and evolution of these unique features, we compared the mitogenomes of three R. phalloides individuals and one individual of a newly discovered congeneric species. These mitogenomes comprise dozens of minicircular chromosomes ([~]2-8 kb), with fairly small mitogenome sizes between 121.1 and 147.5 kb. Each R. phalloides individual contains extremely conserved regions (CRs) on all chromosomes, yet these CRs vary significantly among individuals, suggesting rapid divergence in a concerted manner. In contrast, the congeneric species lacks such CRs. Although nearly identical gene and intron content, there is significant sequence divergence between the two species. Extremely high mitogenome heteroplasmy was observed in all three individuals of R. phalloides and all the variants of protein coding genes are transcribed, but few heteroplasmic variants are shared among the three individuals. No sequence heteroplasmy was detected in the congeneric species. PacBio sequencing revealed concatenated mitochondrial chromosomes in the two species, suggesting rolling circle replication of mitochondrial DNA. We infer that the origins of the CR and sequence heteroplasmy are later than the origin of all-minicircular chromosomes in Rhopalocnemis, and propose a plasmid incorporation model to explain the origin of the CR. The rapid intraspecific variation in mitogenome structure, sequence and heteroplasmy in R. phalloides may result from relaxed selective constraint. The striking heteroplasmy in the R. phalloides mitogenome can not be explained by mitochondrion-targeted DNA-RRR gene loss characterized in this study.

evolutionary biology↗

bioRxiv2025

P2RY2 is a purinergic immune checkpoint linking extracellular ATP to immune evasion and adaptive resistance to immunotherapy

Extracellular ATP (eATP) accumulates substantially in the tumor microenvironment (TME) and rises further during immunotherapy. While canonically an immune-activating "danger" signal, eATP also promotes immunosuppression in tumors, thus far largely attributed to its metabolite, adenosine. Here, we identify direct eATP signaling through P2RY2 as a dominant, adenosine-independent mechanism of immune resistance. Specifically, eATP-P2RY2 signaling serves as the primary upstream driver of COX-1/2 upregulation and consequent accumulation of immunosuppressive PGE2 in the TME, uncovering the long-sought TME-specific trigger of pathological COX-PGE2 hyperactivation in solid tumors. Genetic deletion or pharmacologic inhibition of P2RY2 eliminates both baseline and therapy-induced intratumoral PGE2, restores antitumor T cell responses, and reverses resistance to CAR-T, TCR-T, checkpoint blockade, and TIL therapies. Given that persistently elevated eATP is a hallmark of solid tumors, our work reveals a fundamental mechanism by which tumors hijack innate "danger" signaling to establish immune suppression and develop adaptive resistance to immunotherapy. These findings establish P2RY2 as a purinergic immune checkpoint with translational potential for combinatorial cancer immunotherapies. HIGHLIGHTSO_LIeATP in the TME drives baseline and therapy-induced immune evasion via P2RY2 C_LIO_LIeATP-P2RY2 signaling is the primary cause of PGE2 accumulation in the TME C_LIO_LIP2RY2 propels a feedback loop that enforces adaptive resistance to immunotherapies C_LIO_LIP2RY2 blockade reprograms the TME and restores immunotherapy responsiveness C_LI

immunology↗

bioRxiv2025

Leveraging bioorthogonal conjugation for alpha synuclein fibril surveillance

Alpha synuclein (-syn) amyloid fibrils are associated with various neurodegenerative diseases. To better understand the molecular and cellular basis for -syn fibril persistence and spread, we implemented a fluorophore labeling strategy to surveil pre-formed -syn fibrils in solution and in cells. We leveraged amber codon mediated incorporation of a tetrazine-based artificial amino acid (TetV2.0) to install a cyclooctene-conjugated Janeliaflour, JF549, at four sites on human -syn: residues 4, 60, 96 and 136. Fast coupling occurred under mild buffer conditions and in the presence of the disease-associated cofactor and cytotoxic lipid, psychosine. Labeled fibrils retained their polymorphic features, seeded the growth of new fibrils in vitro, and induced the seeding of positive puncta in -syn FRET biosensor HEK293T cells. This allowed simultaneous tracking of exogenous and endogenous -syn aggregates in biosensor cells, and their localization within the cells. In doing so, our approach facilitates more detailed mechanistic investigation of -syn aggregates.

biochemistry↗

bioRxiv2025

Lactate receptor, HCAR1, in neonatal hypoxic-ischemic encephalopathy

IntroductionHydroxycarboxylic acid receptor 1 (HCAR1) is a G-protein coupled receptor for lactate that is expressed in the brain and plays a role in neuronal excitability, angiogenesis, and repair after injury. Hypoxic-ischemic encephalopathy (HIE) is the most common cause of brain injury and seizures in term neonates. The goal of this study was to describe HCAR1 expression and function in the neonatal brain and further understand its role in HIE. MethodsHCAR1 expression was measured using qRT-PCR in developing mice (postnatal day (p)10, 20, 30, 50). Electrophysiology was used to measure neuronal properties and spontaneous excitatory postsynaptic currents (sEPSC) in hippocampal principal neurons from HCAR1 knockout and wildtype mice when exposed to lactate. Then, p10 HCAR1 knockout and wildtype mice were exposed to hypoxia-ischemia (HI) and placed on electroencephalography (EEG) to compare seizure burden. HCAR1 expression after neonatal HI was measured with PCR. ResultsHCAR1 is expressed at p10 at similar levels to adults (n=6/group; 1-way ANOVA, p<0.0004). Lactate decreases amplitudes and sEPSC frequency in wildtype (p<0.0001, p<0.001) but not HCAR1 knockout mice (p<0.26, p=0.91). After HI, HCAR1 knockout mice have higher seizure burden (2318s in WT vs. 6497s in KO (p=0.04)) and behavioral seizure scores (4 in WT vs. 6 in KO (p<0.001)) than wildtypes. HCAR1 expression increased 24h post-HI but drops to below baseline at 48h post-HI. (n=3/group; p=0.02). ConclusionHCAR1 is expressed on neurons in the developing mouse brain. Lactate decreases neuronal excitability via HCAR1. HCAR1 is upregulated post-HI and mice lacking HCAR1 exhibit worse neonatal HI seizures. HighlightsO_LIHCAR1, a G-protein coupled, lactate receptor is expressed in the developing mouse brain C_LIO_LIHCAR1 is expressed on neurons in the neonatal mouse hippocampus C_LIO_LIHCAR1 is upregulated 24 hours after neonatal hypoxia-ischemia C_LIO_LIMice lacking HCAR1, exhibit worse neonatal hypoxic-ischemic seizures C_LI

neuroscience↗

bioRxiv2025

Embryonic Atrial Injury Programs an Anti-Fibrotic Atrial Fibrillation Substrate

Atrial myopathy is associated with atrial fibrillation in adults, yet the role of embryonic atrial injury in predisposing individuals to atrial fibrillation remains unclear. Using an inducible, cardiomyocyte-specific diphtheria toxin A-mediated injury mouse model, we found that injured embryonic atria exhibited upregulation of apoptosis and TNF signaling pathways, alongside downregulation of calcium handling and atrial fibrillation-associated genes. Single-cell RNA sequencing revealed two distinct cardiomyocyte populations with differential injury responses. Importantly, although myofibroblasts increased in the fibroblast population, these cells displayed an extracellular matrix gene expression profile distinct from the pro-fibrotic phenotype typically observed in fibrillating adult atria and showed no evidence of fibrosis. Concurrently, monocytes/macrophages were activated and showed upregulated expression of the anti-fibrotic factor GPNMB. These findings suggest that adaptive tissue remodeling is counterintuitively prevented from progressing to fibrosis, potentially through GPNMB-mediated mechanisms. This study elucidates molecular pathways linking developmental atrial injury to myopathy and proposes novel strategies to attenuate atrial fibrillation progression.

pathology↗

bioRxiv2025

Lateral septal inhibition of nucleus basalis through direct and indirect pathways in focal limbic seizures

Temporal lobe epilepsy (TLE) is the most common form of epilepsy and is characterized by focal seizures originating from limbic structures, including the hippocampus. Patients with TLE often experience impaired consciousness. A recent awake mouse model study demonstrated decreased cortical cholinergic innervation during focal seizures with impaired consciousness, based on cortical slow wave activity and decreased behavioral responsiveness. But the underlying mechanisms for reduced cortical cholinergic activity are not fully understood. This study employs the same awake mouse model combined with electrophysiology recordings in key network nodes, cell-specific calcium imaging in the lateral septum, and neurotransmitter sensing in one of the major subcortical cholinergic systems, the nucleus basalis of Meynert (NBM). We demonstrate that decreased cortical cholinergic innervation during focal seizures comes from both direct inhibition and indirect de-excitation of the NBM, showing a parallel pathway NBM suppression mechanism from the LS directly and through the paratenial thalamic nucleus indirectly. This work contributes to a deeper understanding of the neural processes involved in impaired consciousness during focal seizures and may open the way to new treatments for this disorder.

neuroscience↗

bioRxiv2025

Machine-learning-based automated Schlemms canal volumetric segmentation for optical coherence tomography

Volumetric segmentation of Schlemms Canal (SC) in optical coherence tomography (OCT) is time-consuming, creating a barrier to experiments studying glaucoma and the anatomy of the trabecular outflow pathways in vivo. To this end, we developed an automated segmentation tool, Schlemms Canal-Localization and Semantic Segmentation (SC-LSS), for the volumetric segmentation of SC in in vivo mice eyes from visible-light OCT (vis-OCT). SC-LSS first localizes the boundaries of SC and subsequently determines the boundaries of SC within the localized region. We used 324 B-scans from 16 mouse eyes for training, validation, and testing the model, and 203 additional B-scans from 16 mouse eyes to evaluate the models accuracy. We found that the Dice coefficient between segmentations generated by SC-LSS and manual expert graders was 0.70 {+/-} 0.20 and that the Dice coefficient between two expert graders was 0.73 {+/-} 0.18 (p = 0.10). Furthermore, SC-LSS captured decreases in SC size with increasing intraocular pressure, yielding a 51.5% decrease in SC size at 20 mmHg compared to 5 mmHg. SC-LSS also identified a 20.1% increase in SC size following the administration of pilocarpine. We anticipate that SC-LSS will accelerate studies on factors regulating the trabecular outflow pathways and their role in glaucoma development and management.

bioengineering↗

bioRxiv2025

Bioinspired Geometry-Encoded Rheotactic Navigation of Sound-Driven Microrobots

Imitating the shape-encoded tactics of natural microswimmers--organisms that flip, roll, and rheotaxis through viscous fluids--could transform microfluidics, micromanufacturing, and targeted therapy. However, translating those geometric navigation cues into actively driven microrobots is an open, largely unexplored challenge. Here, inspired by the structure of sperm cells, we introduce a sound-propelled head-helix microparticle ("microrobot") featuring an elliptical head and a spiral tail. This asymmetrical design interacts with the incident acoustic field, generating complex secondary flows that induce a torque, enabling the particle to reorient around its cross-section. The microparticle exhibits a preferred direction of propulsion and orientation when exposed to a traveling sound wave, reorienting if its initial alignment deviates from this preference. Both the preferred direction and orientation can be modulated by adjusting the sound frequency, and they further adapt to background flow fields in the environment. Furthermore, the microparticle exhibits rheotaxis-like motion, exhibiting wall-following motion with frequency-dependent sliding behavior. By moving towards the channel wall, it enters the region with the smallest flow velocities, allowing it to move antiparallel to the fluid. These findings contribute to the engineering of the trajectories of sound-propelled microparticles and to the development of next-generation microrobots for medical and other innovative applications.

bioengineering↗

bioRxiv2025

Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity

Brain synapses are hotspots of energy consumption, and the synaptic plasticity underlying learning sharply increases this demand. Because most synapses lie far from their cell body, their energy demands must be met locally. A dendritic mitochondrion can extend ~30 m and span many spines, yet ramps up ATP synthesis only near spines undergoing plasticity, providing immediate and sustained energy. Whether structural changes in these juxtaspinal mitochondrial regions (2 m segments at spine bases) support this response is unknown; resolving their energy-producing architecture poses substantial challenges. Compared with the lamellar cristae of axonal mitochondria, dendritic mitochondrial cristae form complex, tubular, and interconnected networks that require multiple high-resolution tomograms to characterize. We therefore developed a correlative light and electron microscopy (CLEM) pipeline with a custom deep-learning model that simultaneously segments five distinct 3D suborganellar structures from limited training data, enabling quantitative analysis across 42 tomograms at 2 nm pixel resolution. We find that juxtaspinal mitochondrial regions are larger than non-juxtaspinal regions within the same mitochondrion and enlarge further during synaptic plasticity. Juxtaspinal mitochondrial ATP synthesis and spine ATP levels rise in parallel; during single-spine plasticity, ATP rises within minutes, before detectable enlargement, indicating that juxtaspinal mitochondrial enlargement sustains rather than initiates the local energy response. The enlarged regions exhibit increased cristae membrane surface area, crista junction number, and membrane area with high curvature, together with increased MIC60 and ATP synthase copies, endoplasmic reticulum contacts, and more proximal ribosomes. Matrix-targeted PKA inhibition reduces MIC60 phosphorylation and impairs juxtaspinal mitochondrial enlargement, plasticity-associated ATP increase, and single-spine plasticity. Together, our findings support a model in which spine-specific remodeling within an individual mitochondrion boosts local metabolic capacity to sustain ATP synthesis and fuel synaptic plasticity.

neuroscience↗

bioRxiv2025

Model of leaf biomass partitioning coefficient in different leaf ranks of rapeseed (Brassica napus L.) main-stem

Leaf growth is a dynamic process, and understanding the number of main-stem leaves and the distribution of leaf biomass at different development stages can provide a theoretical basis for the development of functional-structural rapeseed model. To address the gap in research on the leaf biomass partitioning coefficient model in the crop growth model, we developed the leaf biomass partitioning coefficient model for the main-stem at different leaf ranks in rapeseed. The outdoor experiment with cultivars, Ningyou 18 (V1, conventional), Ningyou 16 (V2, conventional), and Ningza 19 (V3, hybrid), and designed treatment of cultivars x fertilizer x transplanting density in the 2012-2015 growth season. The model was fitted by calculating the ratio of leaf biomass at different leaf ranks on the main-stem to the total leaf biomass on the main-stem, and normalizing the leaf ranks into (0-1] interval. We parameterized the model variables to elucidate how cultivar and environmental conditions influence the leaf biomass partitioning coefficients for different leaf ranks. The descriptive models were validated with independent experimental data, the correlation (r) of simulation and observation values all greater than 0.9 with significant levels at p < 0.001. The absolute values of the average absolute difference (da) are all less than 0.011 g g-1. The ratio of da to the average observation (dap) for the normalized leaf rank, and leaf biomass partitioning coefficient at seedling stage, and budding and bolting stage, and blooming stage, and mature stage are 13.599%, 11.236%, 11.312%, 3.077%, and 8.661%, respectively. The RMSE values are all less than 0.032 g g-1. The models developed in this paper have good performance and reliability for predicting leaf biomass partitioning coefficient of main-stem at different leaf ranks in rapeseed. This study integrates the leaf morphology model of rapeseed with the rapeseed growth model through biomass partitioning, contributing to the development of the functional-structural rapeseed model.

bioinformatics↗

bioRxiv2025

Circulating tumor cell heterogeneity and MMP9 expression in clinical correlation with breast cancer

ObjectivesThis study aimed to investigate the association between the heterogeneity of circulating tumor cell (CTC) subtypes and the expression patterns of matrix metalloproteinase 9 (MMP9) with clinicopathological parameters in breast cancer patients. The distribution of CTC subtypes, MMP9 expression levels, and their influence on tumor progression. MethodsA total of 303 breast cancer patients were enrolled in this study. The association between CTCs subtypes in peripheral blood, MMP9 expression and clinical or pathological data of patients were analyzed. ResultsThe number of mesenchymal CTCs increased significantly with the number of lymph node metastases (P < 0.05), and high MMP9 expression was positively correlated with lymph node involvement (P < 0.05). The proportion of intermediate to high MMP9 expression was significantly higher in mixed CTCs compared to epithelial and mesenchymal CTCs (P < 0.05). High MMP9 expression in tumor tissues was associated with increased CTCs production and induction of epithelial-mesenchymal transition (EMT) (P < 0.05), as well as an elevated number of MMP9-positive CTCs (P < 0.05). ConclusionsThese findings suggest that MMP9 is positively associated with CTCs production and EMT process, and MMP9 may contribute to tumor metastasis by promoting CTC shedding and EMT by degrading the extracellular matrix. We recommend compliance with the Mesh guidelines: https://www.ncbi.nlm.nih.gov/mesh/

cancer biology↗

bioRxiv2025

Electric fields trigger ceramide-dependent budding of exosome vesicles into multivesicular endosomes and boost the generation of exosomes

Exosomes hold immense therapeutic and diagnostic potential, yet their clinical translation remains constrained by low yields. Physiological electric fields (EFs), naturally occurring during wound healing and embryo development, have unexplored roles in exosome biogenesis. Here, we demonstrate that physiological-strength EFs (Direct Current, 50-200 mV/mm) dramatically enhance cellular exosome secretion, achieving a nearly 100-fold increase in a strength-dependent manner. Mechanistically, EFs augmented intraluminal vesicle formation within multivesicular bodies. We proposed a novel EF-driven membrane electroassembly and vesiculogenesis hypothesis and tested it using giant plasma membrane vesicles. We reconstructed EF-induced membrane remodeling and observed EFs driving inward budding of nanoscale exosome-like vesicles. Notably, alternating current EFs (50-400 Hz) exhibited significantly diminished efficacy compared to direct current EFs, highlighting membrane electropolarization-dependent modulation. Pharmacological inhibition of the lipid raft and ceramide almost abolishes EF-induced exosome secretion. Inhibition of the PI3K partially attenuated EF-triggered exosome release. Our findings not only unveil EFs as a potent physiological regulator of exosome secretion but also establish a novel, high-yield production strategy leveraging bioelectric cues. Significant statementWe reported that the bodys natural bioelectricity, the faint electric currents in healing wounds and embryo development, can trigger cells to release 100 times more "natural nanoscale vesicle couriers" called exosomes. This pure physical method is far more efficient than current available technologies, paving the way for breakthroughs in cancer early detection, stem cell therapies, and precision medicine. We found that gentle electric fields can "blow" the cell membrane to release exosomes like "soap bubbles". This explains how bioelectricity controls cell communication during development and wound healing. In short, harnessing the bodys hidden "electric language" unlocks a fast and natural way to mass-produce exosomes.

cell biology↗

bioRxiv2025

Controllable Gap Junctions by Vitamin B12 and Light

Gap junctions, mediate rapid signal transduction between contiguous cells, which are indispensable for multicellular organisms to coordinate cellular activities across numerous physiological processes. However, precise control of gap junctions remains elusive. Herein, we present CarGAP, a single-component chemo-optogenetic tool that utilizes the C-terminal adenosylcobalamin (AdoB12) binding domain of a photoreceptor protein (i.e., CarHC) to achieve reversible control over both vertebrate and invertebrate gap junctions with spatiotemporal precision. The vertebrate CarGAP (i.e., Cx-CarGAP), created by genetically fusing connexins with CarHC in mammalian cells, can efficiently block the gap junction channels through AdoB12-induced protein oligomerization, and subsequently reinstate them via green light-induced protein disassembly. We further introduced the CarGAP system (i.e., Inx-CarGAP) to the Drosophila ovary, enabling reversible control over the heterotypic gap junctions formed by innexin2 (Inx2) and innexin4 (Inx4, also known as zero population growth, Zpg), thereby uncovering the roles of gap junctions in stem cell-niche interactions. This study illustrates CarGAP as a generalizable chemo-optogenetic tool for interrogating the functions of gap junctions in various biological contexts.

bioengineering↗

bioRxiv2025

Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation

Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterise SQ-1, a small-molecule activator of autophagy that targets the prototypical SAR protein p62/SQSTM1 (sequestosome-1). We show that SQ-1 sensitises p62 to oxidation and promotes its disulphide-mediated oligomerisation in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 (NPC1) disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterised by defective autophagy.

cell biology↗

bioRxiv2025

Integrative Multi-Omics Analysis Identifies Nuclear Factor I as a Key Driver of Dysregulated Purine Metabolism in DIPG

Diffuse intrinsic pontine glioma (DIPG) is a devastating brainstem cancer in children, with a median survival of under one year and limited treatment options. Over 80% of DIPGs possess a H3K27M mutation. To identify metabolic vulnerabilities linked to this mutation, we utilized a multi-omics approach in H3K27M-expressing cells, patient-derived cell lines, and mouse models. We show that by reprogramming chromatin landscape the mutation aberrantly induces NFI transcriptional activity, leading to misregulated purine metabolism. The mutation amplifies purine biosynthesis and degradation via the enzymes ATIC and PNP, respectively. Unregulated purine degradation relieves the negative feedback of purines on their own synthesis allowing continuous synthesis, use and degradation making DIPGs reliant on purine biosynthesis. Targeting ATIC reduced tumor progression and improved survival in mice. We propose ATIC as a potential novel target in DIPG.

cancer biology↗

bioRxiv2025

Exploring Population Differences in the Human Gut Microbiome: from Microbial Abundance to Single Nucleotide Polymorphisms

The human gut microbiota exhibits significant diversity across populations, influenced by factors such as geography, diet, and lifestyle, particularly between the Han Chinese and non-Chinese populations. While previous studies have predominantly focused on the taxonomic abundance of the gut microbiome, the impact of single nucleotide polymorphisms (SNPs) in driving population-specific differences remains largely underexplored. In this study, we systematically investigated gut microbial differences between the Han Chinese and non-Chinese populations using the Human Gut Microbiome Reference Genome Catalog (HGMRGC). HGMRGC includes 271,480 non-redundant genomes from 5,785 prokaryotic species, which was generated by metagenomic sequencing data from 9,320 publicly available samples across 22 countries and 3,584 newly sequenced samples from Han Chinese individuals across 29 provinces and regions in China. We observed geography was the primary driver of microbial variation of abundance and SNPs. We identified 625 novel population-specific genome clusters from HGMRGC with functional differences in carbohydrate utilization and 126 species exhibiting distinct prevalence related to vitamin biosynthesis, antibiotic resistance, and carbohydrate metabolism. Beta diversity analysis highlighted significant inter-population differences in both microbial abundance and SNPs, while alpha diversity analysis revealed that non-Chinese populations exhibited higher diversity in microbial abundance, and Han Chinese populations displayed greater diversity in SNPs. These results provide valuable insights into population-specific microbial diversity, laying the groundwork for future research on its functional and health implications.

microbiology↗

bioRxiv2025

A global P-Process map to avoid P-value abuse

P-abuse is serious in difference identification analysis of data. How to avoid P-abuse is a huge challenge. Here, we evolve P-value (a single value) to P-Process (a global landscape of P-values under different sample size) to help researchers correctly recognize and use p-value. We observed -ln(P-Process) after rotation has very similar morphology with Wiener Process (or Brownian motion). Based on this property, for any sample size, we estimated the 95% fluctuation range of P-value and further estimated how many samples (N95()) could make sure 95% of P-values less than the given significant level . Tests proved that the estimation obtains a good performance with only a small number of samples in each group. For broader accessibility, a free web-service, P-Process Map, is available online to show the whole landscape of P-Process. At the end of the article, we explained 10 of the most typical P-abuse problems which can be easily voided by using P-Process. This "rethinking" of P-value from a higher position, which is profoundly different from the way we have seen this for the past century, would yield a new era - 2P era in which hypothesis testing is strongly required to evolve from P-value to P-Process.

bioinformatics↗

bioRxiv2025

Human endogenous retrovirus K (HERV-K) envelope structures in pre- and post-fusion by Cryo-EM

The HERV-K envelope glycoprotein (Env) is aberrantly expressed in diseases including cancers and autoimmune disorders and is targeted by antibodies. The lack of structural information has hindered functional and immune recognition studies. We solved structures of the HERV-K Env in both pre- and post-fusion states with novel monoclonal antibodies using cryo-EM. The pre-fusion Env assembles as a trimer with a distinct fold and architecture compared to other retroviruses, while the post-fusion conformation features a unique "tether" helix within the TM subunit. A panel of monoclonal antibodies, elicited to facilitate structure determination, have been characterized for conformational and subunit specificity, serving as valuable research tools. These findings establish a structural framework for mechanistic studies of HERV-K Env in diseases and evaluation as a potential therapeutic target.

biochemistry↗