Biology subjects

Tanaka, K.

Publications and source records attributed to Tanaka, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Inflammatory signaling drives SQSTM1-dependent suppression of interferon-γ-induced MHC class I

An immune-inflamed tumor microenvironment features interferon-{gamma} (IFN-{gamma}) and inflammatory cytokines, yet how cancer cells integrate these opposing signals to regulate immunogenicity remains poorly understood. Here, we investigated the effect of interleukin-1{beta} (IL-1{beta}) on IFN-{gamma}-induced major histocompatibility complex class I (MHC-I) expression in non-small cell lung cancer (NSCLC) cells. IL-1{beta} suppressed IFN-{gamma}-induced surface MHC-I expression despite preserved or enhanced expression of antigen presentation-related genes, indicating post-transcriptional regulation. This effect emerged 12-24 h after stimulation and accompanied accelerated MHC-I turnover without altering total protein abundance. RNA sequencing identified selective induction of autophagy-related genes under combined IFN-{gamma} and IL-1{beta} stimulation. Immunofluorescence and biochemical analyses demonstrated MHC-I redistribution to autophagosome-lysosome compartments. Mechanistically, the selective autophagy receptor SQSTM1 associated with MHC-I and was required for its surface downregulation, whereas NBR1 depletion and autophagy or lysosomal inhibition failed to restore MHC-I expression, indicating a nonredundant role for SQSTM1. These findings identify post-translational MHC-I trafficking as an underappreciated regulatory layer linking inflammatory signaling to the canonical IFN-{gamma}-MHC-I axis and reveal an SQSTM1-dependent mechanism controlling MHC-I surface availability in immune-inflamed tumors.

immunology↗

bioRxiv2026

A plasma metabolomics workflow for breast cancer detection using quantitative GC/MS and machine learning

Blood-based metabolomic profiling has been widely investigated for breast cancer (BC) detection; however, clinical implementation remains limited due to variability in sample handling, analytical reproducibility, and overfitting during statistical analysis. We established a plasma GC/MS metabolomics workflow for discriminating BC from healthy controls (HC) using conventional machine-learning algorithms. Plasma samples (n = 360; BC = 180, HC = 180) were collected prospectively under standardized preanalytical conditions before surgery and the initiation of systematic anticancer therapy and analyzed using a quantitative GC/MS platform with automated derivatization. Feature selection and model development were conducted using three machine-learning (ML) algorithms (Lasso logistic regression (LR), random forest classifier (RFC), and support vector machine (SVM)). A total of 45 metabolite candidate biomarkers were identified, and the optimal number of metabolite features for each algorithm was estimated by a recursive feature elimination (RFE)-based strategy. The best-performing models achieved area under the ROC curve values (AUC) of 0.910 (LR), 0.893 (RFC), and 0.843 (SVM). We selected prioritizing candidate biomarkers consistently expressed across the multi-algorithm pipeline. A bagging ensemble model improved stability (AUC = 0.911) and reduced false-positive predictions in the independent HC dataset. In addition, model stability with respect to false-positive predictions was assessed using an independent HC cohort (n = 15) that was collected at a separate institution. These results indicate that a plasma metabolomics workflow combined with conventional multi-algorithm ML, algorithm-specific feature selection, and independent assessment provides stable discrimination between BC and HC in a moderately sized cohort.

cancer biology↗

bioRxiv2026

Predicting Neoantigen Immunogenicity from In Vivo Immune Editing

Neoantigen immunogenicity prediction is fundamental to personalized cancer vaccines, tumor-infiltrating lymphocyte (TIL) therapy, and TCR-T cell engineering. Existing computational predictors rely primarily on in-vitro correlates of peptide presentation or models trained against assay-based reactivity, and they are typically validated within a single therapeutic setting. We reasoned that the most direct evidence of neoantigen immunogenicity is longitudinal in-vivo elimination: under immune checkpoint blockade (ICB), subclones bearing recognized neoantigens are selectively depleted over time. Here, we present the Neoantigen Elimination Model (NEMo), a two-compartment (CD8 and CD4) machine learning classifier trained on the in-vivo editing (IVE) of neoantigens across serially sequenced, ICB-treated tumors. By using mechanistically inspired NeoPrecis features designed to capture determinants of immunogenicity beyond MHC binding affinity, NEMo recovered assay-confirmed immunogenic neoantigens across four independent, unseen clinical settings -- pre-existing immunogenicity screening, personalized cancer vaccines, TIL therapy, and a radiotherapy +/- ICB ctDNA cohort -- and stratified progression-free survival more strongly than ELISPOT-confirmed reactivity. The editing signal further revealed an immune-evasion architecture in which oncogenic drivers and neoantigens restricted to lost or silenced HLA alleles are systematically spared from editing.

cancer biology↗

bioRxiv2026

Reduced EEG Complexity and Its Association with Social Communication in Adults with Autism Spectrum Disorder: A Multiscale Entropy Study

Background: Brain functions emerge from temporally organized neural dynamics, and an appropriate level of neural complexity may support flexible information processing. Electroencephalographic (EEG) studies using multiscale entropy (MSE), which quantifies signal complexity across multiple temporal scales, have reported reduced MSE at longer scales in individuals with autism spectrum disorder (ASD). However, most evidence comes from studies of infant and child samples, leaving adult data scarce, and the associations between reduced MSE, clinical symptoms, and social information processing are insufficiently understood. Methods: We recorded and analyzed EEG data from adults with ASD (n = 47) and typically developing (TD) controls (n = 40) during eyes-closed rest and two movie viewing conditions: Inscapes, comprising dynamically changing abstract visual patterns, and Partly Cloudy, an emotionally engaging animated social narrative. Group and condition effects were assessed using cluster-based permutation tests, and associations between MSE and Social Affect (SA) scores from the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), as well as group differences in event-related MSE changes, were examined using linear mixed-effects models. Results: Across conditions, adults with ASD showed lower MSE at longer scales ({tau} = 16-30), corresponding to effective sampling rates of 12.50-6.67 Hz in the coarse-grained time series, than TD adults. Longer-scale MSE within the ASD-TD difference cluster was negatively associated with ADOS-2 SA scores across diagnostic groups. The difference in event-related MSE change between Social and Non-Social conditions, comparing empathic-pain and mentalizing events in Partly Cloudy with temporally matched non-social windows in Inscapes, was smaller in ASD participants than in TD participants. No significant difference between Social and Non-Social windows was observed among ASD participants, whereas TD participants showed significantly greater MSE change during Social than Non-Social windows. Limitations: This study used a modest sample without an independent replication cohort, and the short event windows limited the precision of the MSE estimation. Conclusions: Reduced longer-scale MSE extends to adults with ASD and is associated with higher ADOS-2 SA scores across diagnostic groups. Event-related findings further suggest attenuated differentiation of longer-scale MSE between socially relevant and matched non-social windows in ASD.

neuroscience↗

bioRxiv2026

Androgen receptor determines skeletal muscle sexual dimorphism

The molecular and functional bases of sexual dimorphism in skeletal muscle remain poorly understood. The androgen receptor (AR) is a major regulator of sex-biased gene expression in muscle, but its genomic targets and associated coregulators in vivo are incompletely defined. Using ChIL-seq and an AirID-AR knock-in mouse, we mapped AR-bound genes and AR-associated proteins in skeletal muscle and identified histone deacetylase-linked corepressors. We further identified myosin binding protein H (Mybph) as a female-biased AR-repressed gene conserved in mouse and human muscle. Mybph loss disrupted sarcomeric organization and selectively delayed postinjury force recovery in female mice. These findings define an in vivo AR regulatory network and identify AR-dependent Mybph repression as a potential mechanism contributing to skeletal muscle sexual dimorphism.

molecular biology↗

bioRxiv2026

Circadian temperature compensation is intrinsically linked with metabolism and redox signaling

Circadian rhythms are a universal property of organisms, and a defining property of these oscillators is the ability to maintain a precise period at different temperatures. Indeed, the discovery in the 1950s of this property, known as "temperature compensation," was a watershed event in our understanding of biological timekeeping. Since that time, however, almost no general principles have emerged that uncover the mechanistic basis of how circadian timekeepers defy the rules" of temperature dependence of biochemical reactions. A genetic investigation of circadian temperature compensation revealed that the sensing of metabolism and ensuing modulation of the core mechanism preserves a constant circadian period. Intracellular redox sensing of metabolic rate is intrinsic to this compensation, and this relationship is conserved in bacterial and mammalian cells. These insights explain previously inexplicable observations of the interaction between redox reactions and circadian timekeeping. These results introduce a previously unknown linkage between temperature compensation and metabolism.

cell biology↗

bioRxiv2026

Kif2C safeguards radial glial integrity to prevent cortical malformation

Radial glial cells (RGCs) generate cortical neurons and guide radial neuronal migration, yet how microtubule (MT) regulators coordinate progenitor maintenance, mitotic fidelity, and cortical architecture remains unclear. Here, we identify the MT depolymerase Kif2C/MCAK as an essential regulator of RGC integrity with relevance to human neurodevelopmental disorders. Kif2C is enriched in developing cortical RGCs and localizes to radial fibers, basal endfeet, and mitotic structures. Acute Kif2C depletion in embryonic mouse cortices disrupts RG fiber organization, impairs neuronal migration, reduces the RGC pool, and induces mitotic defects, chromosome segregation errors, DNA damage, and cell-cycle arrest. Kif2C-deficient cortices further exhibit focal pial basement membrane disruption and neuronal overmigration, resulting in a cobblestone-like cortical malformation. We identify two individuals with neurodevelopmental disorders carrying rare deleterious KIF2C variants and show that a patient-derived truncating variant fails to rescue Kif2C-deficient cortical phenotypes, implicating KIF2C dysfunction in human neurodevelopmental disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/726143v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@1970844org.highwire.dtl.DTLVardef@9fe29eorg.highwire.dtl.DTLVardef@d72ddcorg.highwire.dtl.DTLVardef@103f729_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2026

Inhibition of the gut ceramidase Asah2 decelerates the vertebrate ageing rate

The pace of ageing varies markedly among vertebrate species and individuals. However, the mechanisms underlying these differences in ageing rates remain unclear. Here, we show that the activity of the gut ceramidase Asah2 determines species- and strain-specific rates of vertebrate ageing. Comparative genomic analyses of vertebrate species and strains with different ageing rates reveal an association between low Asah2 activity and increased lifespan. Using the ultra-short-lived killifish Nothobranchius furzeri as a model, we demonstrate that knockout of Asah2 (asah2 KO) extends lifespan and attenuates systemic ageing phenotypes, including declines in locomotor activity, abnormal protein accumulation in the brain, and accumulation of senescent cells in the liver. asah2 KO elevates levels of ceramide species with long-chain fatty acids in the intestine, and supplementation with these ceramide species suppresses ageing phenotypes and extends lifespan in wild-type fish. asah2 KO and ceramide supplementation alter gut microbiota composition, and asah2 KO-derived microbiota transplantation attenuates ageing phenotypes, suggesting that reduced Asah2 activity prevents ageing through intestinal ceramide-mediated modulation of the microbiota. Given the evolutionary conservation of the Asah2 gene and its age-dependent upregulation in fish and humans, Asah2 and ceramides may act as ageing accelerators and decelerators, respectively, across animal species.

developmental biology↗

bioRxiv2026

An APP-centered molecular gateway integrates innate immunity and retinoic acid signaling to drive irreversible metamorphic commitment

The mechanisms by which environmental signals induce permanent developmental changes remain a fundamental biological problem. We investigated sea star metamorphosis, where microbial biofilms induce a total body plan reorganization. Using systems biology and functional assays, we identified a three-tiered signaling cascade: sensing, conversion, and execution. The immune adaptor MyD88 senses microbes, while MAPK proteins convert this signal into a retinoic acid developmental cue. An amyloid precursor protein (APP)-centered module acts as the irrevocable commitment gateway, stabilized by a positive feedback loop to ensure irreversibility. Remarkably, the genes driving this transition overlap with human pathways for Alzheimers disease and ADHD/Autism. By defining this ancient neuro-immune axis in an echinoderm adult body plan similar to the chordate head, our study establishes sea star metamorphosis as a model for understanding the evolutionary origins of human neurological disorders from the evolutionary developmental pathology perspective.

developmental biology↗

bioRxiv2026

An integrated scalable process for adherent cultivated meat production: From proliferative cell selection to safety-verified product development

Cultivated meat can contribute to the global food supply; therefore, establishing efficient production processes is an urgent task to meet the growing demand for sustainable protein. Although cell culture technology has historically focused on suspension cells in the pharmaceutical and, subsequently, cultivated meat industries, the development of efficient processes for most adhesion-dependent cells has lagged, with limited examples reported to date. Therefore, this study used primary duck liver-derived adherent cells to develop and evaluate an integrated three-step meat production process involving pre-culture to select highly proliferative cells, packed-bed bioreactor expansion for mass production, and final processing, including packaging and heating. The established process allowed the efficient growth of selected cell populations while maintaining their proliferative characteristics. Moreover, the developed product met the microbiological and heavy metal safety criteria. Comprehensive compositional analysis (nutritional, amino acid, and fatty acid profiles) revealed that the product exhibited a protein profile distinct from that of conventional duck liver paste, along with a unique lower-fat signature. As productivity is dependent on cell doubling time, culture duration and monthly production were estimated for cells from various animal species. Overall, this study established a practical integrated production process for cultivated meat using adherent cells, providing a technological foundation for cellular agriculture applicable to diverse cell types and useful for future food supply diversification. GraphicalAbstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/698307v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@18b1148org.highwire.dtl.DTLVardef@11bbcecorg.highwire.dtl.DTLVardef@102d99org.highwire.dtl.DTLVardef@21af6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Whole-Tissue Distribution Analysis for Visualization of Nanoplastics in the Mouse Brain

Nanoplastics (NPs) are increasingly recognized as environmental contaminants and have been detected in diverse biological tissues; however, their biodistribution in complex organs remains poorly understood. Conventional section-based imaging restricts spatial context and volumetric analysis, making it challenging to map NP distribution in structurally complex organs such as the brain, even with fluorescent labeling. To address these limitations, we developed an integrated workflow combining tissue optical clearing (SeeDB2G) with light-sheet fluorescence microscopy (LSFM), enabling three-dimensional visualization of fluorescently labeled polystyrene (PS) NPs in neonatal mouse brains. At postnatal day 0 - a critical window of heightened vulnerability due to immature barrier systems and rapid neurodevelopment - pups were orally administered spherical PSNPs of 50 or 500 nm. Fluorescence stereoscopic imaging revealed pronounced organ-level accumulation of 50 nm PSNPs in the intestine, liver, kidney, and brain, compared with markedly lower signals from 500 nm PSNPs 24 h post-exposure. Optical clearing rendered the entire brain transparent while preserving fluorescence, allowing LSFM to accurately assess regional PSNP accumulation without sectioning. This workflow enabled whole-brain visualization of size-dependent NP uptake, with 50 nm PSNP detected throughout the brain and the highest accumulation observed in the thalamus and brainstem. Although the current implementation relies on fluorescent labeling and model NPs, this approach provides a scalable platform for whole-organ biodistribution analysis and lays the foundation for mechanistic studies of barrier permeability, developmental vulnerability, and organ-specific interactions.

pharmacology and toxicology↗

bioRxiv2025

Structural Insights into Biased Signaling at Chemokine Receptor CCR7

CC chemokine receptor 7 (CCR7), which orchestrates adaptive immunity, exhibits a phenomenon known as biased agonism. CCL19 induces robust G protein signaling and {beta}-arrestin recruitment, leading to transient signaling. In contrast, CCL21 preferentially activates G protein pathways with minimal arrestin engagement, resulting in sustained signaling and differential functional outcomes. Here, we present the cryo-EM structures of the human CCR7-Gi complex with either CCL19 or CCL21. The structures reveal that while both engage a conserved orthosteric pocket, they adopt markedly distinct binding poses. Notably, the compact 30s loop of CCL21 inserts deeply into the receptors extracellular vestibule, whereas the corresponding loop of CCL19 rests atop extracellular loop 2. Molecular dynamics simulations further reveal that these distinct binding modes induce differential intracellular dynamics, linked to the rotameric state of Y83 at the intracellular end of transmembrane helix 1. We demonstrate that CCL19 stabilizes a flexible conformational ensemble with a highly dynamic helix 8, creating a lateral opening favorable for GPCR kinase engagement. Conversely, CCL21 restricts this flexibility, locking the receptor in a state that precludes kinase interaction while maintaining G protein coupling. Corroborated by functional data, these findings provide key insights into the structural basis of biased agonism at CCR7 and establish a foundation for rational design of pathway-selective immunomodulators. Significance statementChemokine receptor CCR7 directs immune cell migration by activating distinct signaling pathways in response to CCL19 and CCL21, a phenomenon known as biased agonism. The structural basis for this divergence has remained unclear. By combining cryo-electron microscopy with molecular dynamics simulations, we reveal that although both ligands stabilize similar G protein-bound conformations, they drive distinct receptor dynamics. We demonstrate that CCL19 induces a flexible intracellular conformation necessary for recruiting regulatory kinases, whereas CCL21 locks the receptor in a state precluding this interaction. This "dynamic selection" model aligns with functional data and rationalizes a fundamental paradox in chemokine biology, highlighting the critical role of protein dynamics in signal transduction and providing a blueprint for designing precision immunotherapeutics.

biophysics↗

bioRxiv2025

In vitro evaluation of protein-protein interactions in the rice KAI2 ligand signaling complex

KARRIKIN INSENSITIVE 2 (KAI2)/DWARF14-LIKE (D14L) plays key roles in land plant development, environmental responses, and the establishment of arbuscular mycorrhizal symbiosis, likely acting as the receptor for unidentified signaling molecules termed KAI2 ligands (KLs). KL perception by KAI2/D14L promotes DWARF3 (D3)/MORE AXILLARY GROWTH2 (MAX2) F-box protein-mediated ubiquitination of SUPPRESSOR OF MAX2 1 (SMAX1) proteins, thereby transducing the KL signals. Although genetic and in vivo assays have demonstrated the functions of these components, the biochemical details of their interactions remain elusive. Here we investigated physical interactions between rice D14L, D3, and OsSMAX1 in vitro using desmethyl germinone (dMGer), a recently developed KL analog. dMGer elicited KL responses in rice with higher activity and pathway specificity than a widely used KL analog (-)-GR24. dMGer, but not (-)-GR24, directly bound to D14L and promoted the interaction between D14L and D3 in vitro. The interaction between D14L and OsSMAX1 was also enhanced by dMGer. Furthermore, we identified the domain of OsSMAX1 that distinguishes it from its paralog DWARF53 (D53), which is associated with the strigolactone signaling complex. These findings propose a model of the interactions among KL signaling components and highlight the role of the ligand in the signaling complex.

plant biology↗

bioRxiv2025

Latrophilin-2 Orchestrates Endothelial Flow-Mediated Smad1/5 Activation via Endoglin and Shank3

Fluid shear stress (FSS) from blood flow critically determines vascular morphology and function. FSS activates the Smad1/5 pathway maximally at physiological FSS through the BMP9/10 receptors Alk1 and Endoglin to promote vascular stability. We now report that the adhesion G protein-coupled receptor Latrophilin-2 (Lphn2), which mediates flow activation of the canonical junctional complex, is required for flow-mediated Smad1/5 activation in endothelial cells. Lphn2 physically associates with Endoglin and is required for Smad1/5 activation by FSS but not soluble BMP9. This regulation is independent of G-proteins but requires Lphn2s C-terminal PDZ binding motif. Endothelial-specific Lphn2 knockout reduces Smad1/5 activation in mice. In zebrafish embryos, loss of flow or Lphn2 knockout similarly reduced endothelial Smad1/5 activation, with no additive effect, indicating that Lphn2 mediates flow-induced activation in vivo. APEX2 proximity labeling revealed that the PDZ domain-containing scaffold protein Shank3 associated with Lphn2 under flow. Shank3 knockdown blocked flow-induced Smad1/5 activation in vitro and Shank3 global knockout mice exhibited reduced endothelial nuclear Smad1/5 and increased susceptibility to arteriovenous malformations. Lphn2 thus mediates flow-induced Smad1/5 activation and vessel stabilization through the scaffold protein Shank3, independently of G proteins. Together with the accompanying paper on Notch1, we conclude that Lphn2 confers FSS sensitivity to three of the major FSS pathways via distinct mechanisms.

cell biology↗

bioRxiv2025

Latrophilin mediates flow activation of Notch to control vascular endothelial phenotype and atherosclerosis

Fluid shear stress (FSS) is a major determinant of endothelial cell (EC) phenotype, with physio-logical laminar FSS promoting arterial identity and stability, and disturbed FSS promoting atherosclerosis. We previously identified the adhesion G protein-coupled receptor (GPCR) Latrophilin-2 (LPHN2) as a junctional protein required for FSS activation of the PECAM1/VE-cadherin/VEGFR2/PlexinD1 junctional mechanosensory pathway, which regulates EC alignment to laminar blood flow and promotes EC inflammatory activation and atherogenesis under disturbed flow. Here, we demonstrate that Lphn2 endothelial cell-specific knockout hyperlipidemic mice develop larger atherosclerotic plaques than controls--opposite from the previously reported Pecam1 knockout model. Transcriptomic analysis revealed that LPHN2 contributes more than half of flow-responsive gene expression and suppresses pro-inflammatory pathways. Critically, LPHN2 is essential for FSS-induced Notch1 activation to suppress inflammation, via a GPCR-independent mechanism. Active Notch correlates with physical association of LPHN2 with Notch1 activator, {gamma}-secretase, and Notch1 in response to flow. Both the Notch1 intracellular domain (NICD) and transmembrane domain (NTMD) contribute to the anti-inflammatory gene program, with the non-canonical NTMD signaling specifically suppressing the pro-inflammatory YAP pathway. Together with the accompanying paper showing that LPHN2 also mediates flow activation of the Smad1/5 pathway, these data identify LPHN2 as a central mediator of EC flow responses through multiple independent mechanisms in vascular biology and disease.

molecular biology↗

bioRxiv2025

Human fibroblasts from aged individuals exhibit chromosomal instability through replication stress caused by oxidative stress

Aneuploid cells are known to increase with age. Previously, we demonstrated that aneuploid cells increase in fibroblasts from aged mice due to chromosomal instability (CIN), which is caused by oxidative stress. It is unclear whether this phenomenon also occurs in human cells, which are more resistant to oxidative stress than mouse cells. Here, we found that fibroblasts from aged individuals exhibited an increase in aneuploid cells. The frequency of chromosome missegregation and micronuclei increased in these cells, indicating CIN. A DNA fiber assay revealed the presence of replication stress, accompanied by an increase in 53BP1 nuclear bodies and ultrafine bridges. Increased levels of reactive oxygen species derived from mitochondria, along with reduced mitochondrial membrane potential, imply that these cells experienced oxidative stress due to mitochondrial functional decline. Antioxidant treatment reduced the frequency of chromosome missegregation and micronuclei, suggesting that oxidative stress causes CIN. Oxidative stress also causes replication stress, which precedes CIN. Spindle microtubules were stabilized in fibroblasts from aged individuals, which was alleviated by antioxidant treatment. Taken together, these findings suggest that aging-related CIN in human fibroblasts is caused by oxidative stress associated with mitochondrial dysfunction, which induces replication stress that in turn causes CIN through microtubule stabilization. Although human fibroblasts are more resistant to the ambient oxygen environment than mouse fibroblasts, our findings showed that they undergo oxidative stress that causes CIN with age in a manner similar to mouse fibroblasts, revealing a conserved phenomenon in mammalian cells.

cell biology↗

bioRxiv2025

Hypomorphic Lig4 gene mutation in mice predisposes to Th1-skewing intestinal inflammation

Dysregulation of DNA double-strand break (DSB) repair leads to adaptive immunodeficiency, whereas the remaining lymphocytes are aberrantly activated and provoke inflammations. However, no model mice were available to consistently manifest inflammation under defective DSB repair. We generated mutant mice carrying a missense mutation p.W447C in the gene encoding DNA ligase IV (LIG4), critical for DSB repair. Lig4W447C/W447C mice showed growth retardation and severe intestinal inflammations under adaptive immunodeficiency. The inflammations were featured by marked infiltration of T helper type 1 (Th1) cells and macrophages and was dependent on lymphocytes. When Ifng was deleted, Th2 and Th17 instead of Th1 cells drove the inflammations. Lig4W447C/W447C mice showed expansion of oligoclonal T cells with T cell receptor repertoire skewed towards more proximal 3 V and 5 J gene segments. Thus, our novel hypomorphic Lig4 mutant mice show that defective DSB repair leads to Th1-dependent intestinal inflammations under severe adaptive immunodeficiency.

immunology↗

bioRxiv2025

Ubiquitination-activated TAB-TAK1-IKK-NF-kB axis modulates gene expression for cell survival in the lysosomal damage response

The lysosomal damage response is important for the maintenance of cellular homeostasis. Although the mechanisms underlying the repair and autophagic elimination of damaged lysosomes have been elucidated, the early signal transduction pathways and genes induced in response to lysosomal damage remain elusive. We performed transcriptome and proteome analyses and found that the TAB-TAK1- IKK-NF-{kappa}B axis is activated by K63-linked ubiquitin chains that accumulate on damaged lysosomes. This activates the expression of various transcription factors and cytokines that promote anti-apoptosis and intercellular signaling. The findings highlight the crucial role of ubiquitin-regulated signal transduction and gene expression in cell survival and cell-cell communication in response to lysosomal damage. The results suggest that the ubiquitin system is not only involved in the removal of damaged lysosomes by lysophagy, but also functions in the activation of cellular signaling for cell survival.

cell biology↗