Biology subjects

Xia, W.

Publications and source records attributed to Xia, W..

At least 19 recordsLinked to original sources

bioRxiv2026

Effects of Alternating Polarity Frequency on the Assembly of Electro-Methanogenic Microbial Communities

Electro-methanogenesis can enhance methane production and has attracted extensive interest, but the current strategies for building electro-methanogenic microbial communities suffer from several limitations. Alternating polarity has been shown as a new strategy to build electro-methanogenic communities, but the impact of alternation frequency on community assembly remains to be understood. In this study, the impact was evaluated using bioelectrochemical systems amended with granular activated carbon, and the working-electrode potential was alternated between +0.4 and -0.4 V vs. SHE at six frequencies ranging from 0.5 to 12 days. Among the tested conditions, 4-d alternation led to the best overall performance, producing approximately 250 L/L/kg cumulative biogas, 96% methane content, and a 45% methane yield, while preserving a stable and reproducible community structure. The community contained two Methanobacterium populations, two putatively electroactive Geobacter populations, and one putatively electroactive Pseudomonas population, together with diverse fermentative and syntrophic bacteria. Transcript-based analyses revealed clear frequency- and potential-dependent shifts in the activity of these functional groups. Redundancy analysis associated the Methanobacterium formicicum-related population with cathodic current and methane production, whereas the Geobacter sulfurreducens-related population was linked to anodic current and methane production. Bayesian and local-similarity networks further connected methanogen dynamics with specific electroactive, fermentative, and syntrophic partners. Collectively, these results establish alternating polarity frequency as a critical parameter for building robust communities capable of high-rate, high-quality methane production.

microbiology↗

bioRxiv2026

Targeted tumor desialylation by engineered probiotic reprograms the tumor microenvironment to potentiate immunotherapy

Tumor hypersialylation drives immunosuppression and limits immunotherapy efficacy by shielding tumor cells and engaging inhibitory immune receptors. Here, we engineered Escherichia coli Nissle 1917 (EcN{Delta}pgi-SAS) as a metabolically confined "desialylation catalyst" to remodel the tumor microenvironment. This strain combines HER2-directed adhesion, hypoxia-inducible surface sialidase display for targeted glycan cleavage, and sialic acid catabolism to prevent glycolytic recycling. Critically, disrupting glucose metabolism ({Delta}pgi) restricts bacterial proliferation to sialic acid-rich tumor microenvironment, significantly enhancing biosafety. In mice, EcN{Delta}pgi-SAS colonized tumors and effectively desialylated tumor cells, synergizing with anti-PD-L1 to suppress growth of immunologically "cold" tumors. Mechanistically, desialylation reversed immunosuppression by broadly enhancing antitumor immunity. Orally administered EcN{Delta}pgi-SAS substantially inhibited colorectal carcinogenesis, repaired epithelial barrier integrity by restoring tight junctions, and prevented adenoma formation. This integrated strategy establishes a clinically translatable platform for reversing immunosuppression in solid tumors.

synthetic biology↗

bioRxiv2026

Parental B-MYB/FOXM1 controls mitotic E2F to determine daughter cell fate

Mitogens trigger cell-cycle entry by activating E2F at the restriction point, which is followed by B-MYB/FOXM1 activation and progression to mitosis. How mitogens control continued cycling and cell-cycle exit after the restriction point is not well-understood. By developing an E2F and B-MYB/FOXM1 dual transcriptional biosensor system, we show that S/G2 phase duration is set by timed mitogen-regulated B-MYB/FOXM1 activation, while E2F activity gradually declines before mitosis. As a striking consequence, rapid B-MYB/FOXM1 activation shortens S/G2, delivering high mitotic E2F activity to daughter cells which keeps them cycling. Delayed B-MYB/FOXM1 activation prolongs S/G2, depleting mitotic E2F which drives daughters to quiescence. When S/G2 is further prolonged, partially activated B-MYB/FOXM1 frequently reverts, triggering mitotic bypass and polyploid quiescence. Thus, B-MYB/FOXM1 governs a tri-directional (G2 restriction point) where cells commit to continued cycling through early B-MYB/FOXM1 activation; cell-cycle exit through delayed B-MYB/FOXM1 activation; or mitotic bypass by B-MYB/FOXM1 inactivation.

cell biology↗

bioRxiv2026

Polymicrobial catheter biofilms sustain susceptible Enterococcus faecalis and Escherichia coli during β-lactam treatment

Broad-spectrum {beta}-lactam exposure can select for Enterococcus-dominated urinary communities in catheterized intensive-care patients, even when co-colonizing Escherichia coli remains susceptible. We investigated paired E. faecalis and E. coli isolates recovered before and after piperacillin-tazobactam (TZP) treatment using a catheter biofilm model and showed that their survival depends on mutualism and biofilm-dependent persistence. Without antibiotics, E. faecalis reduced E. coli biofilm formation yet promoted pre-attachment co-aggregation and reorganized mixed-biofilm architecture on the catheter. Despite TZP susceptibility and the absence of resistance determinants, catheter-associated biofilms and biofilm-dispersed cells survived concentrations 250- to 1000-fold above their MICs, whereas planktonic cells were eliminated. Survivors retained susceptibility but showed delayed regrowth, consistent with a transient persister-like state. In the post-treatment pair, each species sustained the other during recovery, coinciding with a nonsynonymous substitution in the enterococcal surface adhesin Esp. These findings show that antagonistic and cooperative interactions can coexist within catheter biofilms and enable susceptible polymicrobial communities to withstand {beta}-lactam treatment without {beta}-lactam resistance.

microbiology↗

bioRxiv2026

NLRX1 is an essential, druggable regulator of mitochondrial permeability transition

The molecular composition of the mitochondrial permeability transition pore (mPTP) remains contested, and several efficacious mPTP inhibitors act through undefined, cyclophilin D (CypD)-independent targets. Using two structurally distinct chemotypes of optimised, brain-penetrant mPTP inhibitors as chemical probes, we applied affinity-based chemoproteomics to identify the mitochondrial NOD-like receptor NLRX1 as their shared target. Both chemotypes bind NLRX1, and binding potency across a compound series tracks mPTP-inhibitory activity. Using CRISPR-Cas9-edited human cells and Nlrx1-/- mouse tissues, we show that NLRX1 is required for normal calcium-induced mPTP opening: its loss raises the calcium threshold for pore opening and its overexpression lowers it, independently of CypD. NLRX1 associates with postulated mPTP components, including ATP synthase and the adenine nucleotide translocase, in a compound-sensitive manner, and sustains mitochondrial protein homeostasis over longer timescales. The lead compound, GSK900, is orally bioavailable, brain-penetrant, and active in an mPTP-sensitive neurological injury model. These findings, converging with recent genetic studies, establish NLRX1 as an essential, CypD-independent regulator of mitochondrial permeability transition and provide brain-penetrant chemical tools to interrogate this biology.

cell biology↗

bioRxiv2026

Structural and Dynamic Basis of TREM2--DAP12 Stabilization by Small-Molecule Agonist VG-3927

Triggering receptor expressed on myeloid cells 2 (TREM2) is an important microglial receptor implicated in Alzheimers disease, but the structural basis of small-molecule TREM2 agonism remains poorly understood. In particular, the clinical-stage agonist VG-3927 has been reported to promote TREM2-DAP12 complex formation, suggesting a mechanism distinct from conventional recognition at the ectodomain surface. Here, we propose that VG-3927 binds within a membrane-embedded interfacial cavity formed by the transmembrane helices of TREM2, DAP12A, and DAP12B. Our simulations support a stable and reproducible cavity-bound pose that is maintained across independent trajectories and is anchored by a persistent hotspot network dominated by hydrophobic and van der Waals interactions. Rather than merely occupying a pre-existing pocket, VG-3927 reshapes the surrounding transmembrane assembly by reinforcing selected interhelical contacts, strengthening receptor-adaptor hydrogen-bond coupling, and biasing the three-helix bundle toward a more compact, more upright, and more conformationally focused state. Importantly, the ligand-bound ensemble remains within a subdomain of the apo conformational landscape, consistent with stabilization of a pre-existing but less populated signaling-relevant state. Together, these findings support a membrane-asscosiated mechanism in which VG-3927 acts as a transmembrane interfacial molecular glue, biasing the TREM2-DAP12 complex toward a more compact, ordered, and signaling-competent state. This finding can provide a structural framework for understanding small-molecule TREM2 agonism.

Molecular Biology↗

bioRxiv2026

Environmental gradients shape climate adaptive phenotypes in Muscovy ducks in Benin with implications for adaptation policy.

Climate change threatens livestock-dependent livelihoods across sub-Saharan Africa, yet National Adaptation Programmes of Action (NAPAs) and Nationally Determined Contributions (NDCs) rarely incorporate animal genetic resource management despite explicit mandates under the Convention on Biological Diversitys Global Plan of Action for Animal Genetic Resources. This study addresses this policy gap by investigating how environmental gradients shape phenotypic adaptation in Muscovy duck (Cairina moschata) populations across Benins three agroecological zones, generating evidence to inform climate-responsive livestock policy. We surveyed 505 farmers and characterized 1,300 ducks across dry (Temperature-Humidity Index [THI]: 70-74), sub-humid (THI: 74-78), and humid (THI: 78-82) zones. Climate analysis confirmed accelerating thermal stress (+0.38 degrees C per decade in humid zones), exceeding IPCC West African projections and threatening Sustainable Development Goal 2 (Zero Hunger) targets. Principal component analysis revealed zone-specific phenotypic clustering (57.9% variance explained), with thermoregulatory traits showing coordinated adaptation: body volume-surface ratios 42.7% lower in humid zones (p = 0.002), limb proportions 72.7% higher (p < 0.001), and white feather coverage 31.3% greater (p = 0.019). Reproductive performance declined significantly along the thermal gradient (lifetime production: 40.7 vs. 37.1 eggs; p < 0.001), quantifying climate-driven productivity losses relevant to national food security assessments. Phenotype-climate associations demonstrated that locally adapted variants (black-white pied in dry zones; white-black-green pied in humid zones) maintain superior fitness under native conditions, providing critical evidence for the breed-for-environment approach advocated by FAOs Climate-Smart Agriculture framework. These findings provide an empirical foundation for incorporating animal genetic resource conservation into Benins NDC implementation, ECOWAS regional livestock strategies, and the African Unions Comprehensive Africa Agriculture Development Programme (CAADP) climate resilience targets.

evolutionary biology↗

bioRxiv2025

Three transcription factors coordinate the archaeal cell cycle progression through a regulatory braking point mechanism

Archaea of the order Sulfolobales execute a well-structured cell cycle program similar to that of eukaryotic cells. However, unlike eukaryotes, archaea lack cyclins and cyclin-dependent kinases and thus the mechanism of cell cycle regulation remained enigmatic. Here, we show that three essential ribbon-helix-helix domain transcription factors, namely, aCcr1, aCcr2, and aCcr3, play pivotal roles in controlling the cell cycle progression in the thermoacidophilic archaeon Saccharolobus islandicus. Coordinated expression of aCcr1 during M-G1 phase, aCcr3 during G1-S phase, and aCcr2 throughout the cell cycle ensures the timely transcription of the key genes that define the cell cycle phases. These include genes involved in chromosome dimer resolution, chromosome segregation, cell division, chromatin organization, DNA replication and repair, protein phosphorylation and degradation and metabolisms of amino acids, tRNA and carbohydrates. The synergy between aCcr1, aCcr2, and aCcr3 is achieved through their differencial affinities for the promoters and the levels of protein expression. We propose that the global regulation of the Sulfolobales cell cycle may be achieved not through transcriptional activation, but rather by repression of the key genes during strategic moments of the cell cycle. We propose a braking point model for the cell cycle control in Sulfolobales, which may represent a simple evolutionary intermediate on the way to the more complex cell cycle regulation in eukaryotes.

microbiology↗

bioRxiv2025

Structural insights and engineering of deep-sea halophilic PET hydrolytic enzymes

Pervasive use of polyethylene terephthalate (PET) poses tremendous challenges for global waste management and environmental sustainability, fueling growing interests in enzymatic degradation as an eco-friendly solution. While PET hydrolases hold significant promise, their industrial deployment is hindered by insufficient performance, particularly under high-salinity conditions raised from high substrate loads. Building on our previous discovery of three deep-sea PET hydrolases (dsPETase01, dsPETase05 and dsPETase06) with exceptional halophilicity and PET-degrading activity, we here present their three-dimensional structures and mechanistic characterization. Structural comparison, site-directed mutagenesis, and domain swapping reveal key structural features and the essential role of C-terminal acidic residues in salt tolerance. Integrating semi-rational protein design, Transformer-based modeling, and disulfide bond engineering, we synergistically enhance the thermostability and catalytic efficiency of dsPETase05. These findings elucidate the unique structural features and salt adaptation mechanisms of deep-sea halophilic PET hydrolases, and inform the future engineering of biocatalysts for application in harsh industrial environments.

molecular biology↗

bioRxiv2025

Longitudinal Imaging of Experimental Intracerebral Hemorrhage Pathology with Iodine-enhanced Micro-CT

BackgroundIodine-enhanced micro-computed tomography (Micro-CT) enables high-resolution three-dimensional imaging of brain architecture. This study aimed to characterize both acute and chronic pathological changes following intracerebral hemorrhage (ICH) using iodine-enhanced micro-CT. MethodExperimental ICH was induced in 8- to 10-week-old C57BL/6 mice (n = 76) via stereotaxic injection of either 0.075 U collagenase IV or 30 l autologous blood. Iodine-enhanced micro-CT imaging was performed at 4 hours, 1, 3, and 7 days after intracerebral hemorrhage post-ICH to evaluate hematoma formation and erythrolysis. Chronic alterations, including ventriculomegaly and ipsilateral lesion, were assessed at 28 days post-ICH. In parallel, MRI was conducted at 1, 7, and 28 days following autologous blood injection, followed by micro-CT, to facilitate cross-modality quantitative analysis. Lesion volumes were compared between imaging modalities over time. ResultsMicro-CT enabled quantification of hematoma volume and erythrolysis in ICH models. Hematomas extended along perivascular pathways toward the cerebral surface in both collagenase- and autologous blood-induced ICH models. At 28 days post-ICH, micro-CT detected ventriculomegaly and hypodense lesions without concurrent expansion of the choroid plexus. Lesion volume measurements derived from micro-CT correlated with those from MRI, enabling quantitatively assessment of iron deposition and hematoma size alterations after ICH. ConclusionIodine-enhanced micro-CT provides a robust and high-resolution imaging platform for evaluating hematoma evolution, hemolysis, ventricular enlargement, and chronic brain lesions in experimental ICH. When integrated with MRI, these multimodal imaging approaches enhance the characterization of both hematoma volume and iron deposition following ICH.

neuroscience↗

bioRxiv2025

Quantifying Protein-Protein Interaction with a Spatial Attention Kinetic Graph Neural Network

Accurate prioritisation of near-native protein-protein interaction (PPI) models remains a major bot-tleneck in structural biology. Here we present SAKE-PP, a physics-inspired, spatial-attention equivariant graph neural network that directly regresses interface RMSD (iRMSD) without any native references. Trained on docking decoys generated through our novel hierarchical sampling strategy applied to PDB-Bind dataset, SAKE-PP combines force-field-like attention with Laplacian-eigenvector orientation to couple local interaction forces with global topology. On the 2024PDB benchmark comprising 176 het-erodimers, SAKE-PP demonstrates effective optimization and selection of AF3 decoys, achieving improvements of 13.75% based on iRMSD statistics and 12.5% based on DockQ scores. It consistently outperforms the AF3 ranking score in multiple metrics, including overlap, hit rate, and correlation. In zero-shot evaluation of 139 antibody-antigen complexes, SAKE-PP improves the score-iRMSD correlation by 0.4. By unifying geometric deep learning with physics-based realism, SAKE-PP provides a robust, plug-and-play scoring function that streamlines reliable PPI evaluation and accelerates downstream structure-guided drug-design workflows.

bioinformatics↗

bioRxiv2024

Efficient degradation of oxidized polyethylene containing ester bonds by cutinase or lipase in aqueous phase

Polyethylene (PE) plastics are extensively utilized across agricultural, industrial, and medical sectors owing to their favorable physicochemical properties. However, their chemical stability and escalating production have resulted in severe waste accumulation and environmental pollution. Conventional disposal methods are plagued by resource inefficiency and secondary pollution. While emerging strategies offer promise, physicochemical methods demand harsh operating conditions, and biological routes remain inefficient. This research presents an integrated "chemical pretreatment-biodegradation-upcycling" system that combines the efficiency of chemical catalysis with the sustainability of biological conversion. Ester bonds were introduced into PE via Baeyer-Villiger oxidation, followed by enzymatic hydrolysis using the cutinase from Thermobifida fusca WSH03-11 (TfCut). Specifically, machine learning-aided optimization of reaction conditions and computational redesign of TfCut enhanced degradation efficiency, yielding a maximum weight loss of approximately 71.19%. The degradation intermediates were bio-converted into poly(3-hydroxybutyrate) (PHB) by the wild-type strain LETBE-HOU, isolated in this study, achieving a concentration of 16.75 mg/L. Multi-omics analysis of LETBE-HOU further revealed the PHB biosynthesis pathway and fatty acid degradation regulation. This work breaks the long-standing reliance on physiochemically-derived degradation intermediates for microbial conversion of PE, establishing a fully circular system that opens new avenues for future research.

biochemistry↗

bioRxiv2024

Imaging-Guided Metabolic Radiosensitization of Pediatric Rhabdoid Tumors

Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRT). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved anti-malarial drug, Atovaquone (AVO). We then establish the utility of Oxygen-Enhanced-Multispectral Optoacoustic Tomography (OE-MSOT), a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment which results in complete elimination of tumors in all tested mice when combined with 10 Gy radiotherapy, a dose several times lower than the current clinic standard. Finally, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual clinical patient population. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.

bioengineering↗

bioRxiv2024

Building Predictive Understanding of Microbial Ecology by Bridging Microbial Growth Kinetics and Microbial Population Dynamics

Modeling microbial communities can provide predictive insights into microbial ecology, but current modeling approaches suffer from inherent limitations. In this study, a novel modeling approach was proposed to address those limitations based on the intrinsic connection between the growth kinetics of guilds and the dynamics of individual microbial populations. To implement the modeling approach, 466 samples from four full-scale activated sludge systems were retrieved from the literature. The raw samples were processed using a data transformation method that not only increased the dataset size by three times but also enabled quantification of population dynamics. Most of the 42 family-level core populations showed overall dynamics close to zero within the sampling period, explaining their resilience to environmental perturbation. Bayesian networks built with environmental factors, perturbation, historical abundance, population dynamics, and mechanistically derived microbial kinetic parameters classified the core populations into heterotrophic and autotrophic guilds. Topological data analysis was applied to identify keystone populations and their time-dependent interactions with other populations. The data-driven inferences were validated directly using the Microbial Database for Activated Sludge (MiDAS) and indirectly by predicting population abundance and community structure using artificial neural networks. The Bray-Curtis similarity between predicted and observed communities was significantly higher with microbial kinetic parameters than without parameters (0.70 vs. 0.66), demonstrating the accuracy of the modeling approach. Implemented based on engineered systems, this modeling approach can be generalized to natural systems to gain predictive understandings of microbial ecology.

microbiology↗

bioRxiv2024

Hexa-acylated lipopolysaccharides from the gut microbiota enhance cancer immunotherapy responses

Immune checkpoint inhibitors (ICI), such as anti-PD-1, have revolutionized cancer treatment, but they are only effective for a minority of patients. The gut microbiome plays a crucial role in modulating immunotherapy treatment responses, and previous studies correlated lipopolysaccharide (LPS)-producing gut microbes with poorer prognosis. However, LPS from diverse bacterial species have activities ranging from immunostimulatory to inhibitory. By functionally analyzing fecal metagenomes from 112 melanoma patients prior to anti-PD-1 therapy, we found that a subset of LPS-producing bacteria encoding immunostimulatory hexa-acylated LPS was enriched in the microbiomes of clinical responders. We confirmed robust activation of the NF-kB pathway by hexa-acylated LPS in vitro, and this activation was significantly inhibited by penta-acylated LPS in a dose-dependent manner. Importantly, oral administration of hexa-acylated LPS augmented anti-PD-1-mediated anti-tumor immunity in an in vivo mouse model of cancer immunotherapy. Microbiome hexa-acylated LPS may therefore represent an accessible predictor and potential enhancer of clinical anti- PD-1 immunotherapy responses. Statement of significanceFunctional rather than taxonomic profiling of patient gut microbiomes reveals hexa-acylated LPS as a novel biomarker of responsiveness and a targetable pathway for enhancing responses to anti-PD-1, informing future studies and current patient treatment.

microbiology↗

bioRxiv2024

ApoE ϵ4-dependent alteration of CXCR3+CD127+ CD4+ T cells is associated with elevated plasma neurofilament light chain in Alzheimer's disease

Recent findings indicate a correlation between the peripheral adaptive immune system and neuroinflammation in Alzheimers disease (AD). To characterize the composition of adaptive immune cells in the peripheral blood of AD patients, we utilized single-cell mass cytometry (CyTOF) to profile peripheral blood mononuclear cells (PBMCs). Concurrently, we assessed the concentration of proteins associated with AD and neuroinflammation in the plasma of the same subjects. We found that the abundance of proinflammatory CXCR3+CD127+ Type 1 T helper (Th1) cells in AD patients was negatively correlated with the abundance of neurofilament light chain (NfL) protein. This correlation is apolipoprotein E (ApoE) {varepsilon}4-dependent. Analyzing public single-cell RNA-sequencing (scRNA-seq) data, we found that, contrary to the scenario in the peripheral blood, the cell frequency of CXCR3+CD127+ Th1 cells in the cerebrospinal fluid (CSF) of AD patients was increased compared to healthy controls (HCs). Moreover, the proinflammatory capacity of CXCR3+CD127+ Th1 cells in the CSF of AD patients was further increased compared to HCs. These results reveal an association of a peripheral T-cell change with neuroinflammation in AD and suggest that dysregulation of peripheral adaptive immune responses, particularly involving CXCR3+CD127+ Th1 cells, may potentially be mediated by factors such as ApoE {varepsilon}4 genotype. One sentence summaryAn apolipoprotein E (ApoE) {varepsilon}4-dependent alteration of CD4 T cell subpopulation in peripheral blood is associated with neuroinflammation in patients with Alzheimers disease.

immunology↗

bioRxiv2024

Revolutionizing GPCR-Ligand Predictions: DeepGPCR with experimental Validation for High-Precision Drug Discovery

G-protein coupled receptors (GPCRs), crucial in various diseases, are targeted of over 40% of approved drugs. However, the reliable acquisition of experimental GPCRs structures is hindered by their lipid-embedded conformations. Traditional protein-ligand interaction models falter in GPCR-drug interactions, caused by limited and low-quality structures. Generalized models, trained on soluble protein-ligand pairs, are also inadequate. To address these issues, we developed two models, DeepGPCR_BC for binary classification and DeepGPCR_RG for affinity prediction. These models use non-structural GPCR-ligand interaction data, leveraging graph convolutional networks (GCN) and mol2vec techniques to represent binding pockets and ligands as graphs. This approach significantly speeds up predictions while preserving critical physical-chemical and spatial information. In independent tests, DeepGPCR_BC surpassed Autodock Vina and Schrodinger Dock with an AUC of 0.72, accuracy of 0.68, and TPR of 0.73, whereas DeepGPCR_RG demonstrated a Pearson correlation of 0.39 and RMSE of 1.34. We applied these models to screen drug candidates for GPR35 (Q9HC97), yielding promising results with 3 (F545-1970, K297-0698, S948-0241) out of 8 candidates. Furthermore, we also successfully obtained 6 active inhibitors for GLP-1R. Our GPCR-specific models pave the way for efficient and accurate large-scale virtual screening, potentially revolutionizing drug discovery in the GPCR field.

bioinformatics↗

bioRxiv2023

Nuclear cytoophidia assembly represses transcriptional activity to control skeletal development and homeostasis

Compartmentation via filamentation is an evolutionarily conserved subcellular structure that fine-tunes the inherent activity of proteins. Cytoophidia represent a typical class of filamentous structures controlling enzymatic activities. Despite eukaryotic cells containing both cytoplasmic cytoophidia and nuclear cytoophidia, the physiological significance of nuclear cytoophidia is largely unknown. Here we show that nuclear filamentation inhibits the transcriptional activity of Impdh2 required for limb formation and bone resorption. Impdh2 deletion in mouse limb mesenchymal progenitors causes severe skeletal dysplasia by impairing endochondral ossification and chondrocyte differentiation. Additionally, Impdh2 deficiency in myeloid lineages leads to an increased bone mass via impeding osteoclast differentiation. Furthermore, Impdh2 regulates osteoclastic mitochondrial biogenesis and function. We propose that the nuclear compartmentalization of Impdh2 regulates the transcriptional activity during skeletal development and homeostasis.

cell biology↗