Biology subjects

Fujiwara, Y.

Publications and source records attributed to Fujiwara, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Accumulation of two distinct alleles causes astringency loss in cultivated polyploid persimmon

Persimmon fruit accumulates high levels of proanthocyanidins (PAs), causing extreme astringency. In pollination-constant and non-astringent (PCNA) cultivars, PA accumulation ceases early in fruit development. Although the PCNA trait is recessively controlled by the ASTRINGENCY (AST) locus, its causal gene has remained unknown. Using haplotype-resolved forward genetics in a hexaploid genetic background, we identified the previously uncharacterized TANNIN (TAN) as the causal gene. Long-read sequencing revealed that PCNA originated through the accumulation of independently derived ast alleles that cause transcriptional deficiency of TAN. These findings resolve the complex genetic basis of natural astringency loss in persimmon and provide a framework for molecular breeding. Further investigation of TAN function would uncover mechanisms underlying massive accumulation of PAs in persimmon fruit and insight into specialized metabolite sequestration.

plant biology↗

bioRxiv2026

Gingipain-containing products from Porphyromonas gingivalis promote epithelial CCL20 signaling and γδ T-cell accumulation in COPD-like airways

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disease in which impaired mucosal barrier function may increase susceptibility to aspirated oral microbial products. Periodontal disease has been associated with COPD development and exacerbation, but the epithelial mechanisms linking periodontal pathogens to pulmonary immune remodeling remain unclear. Here, we investigated whether gingipain-containing Porphyromonas gingivalis culture supernatant (PCS) promotes {gamma}{delta} T-cell-associated inflammation in COPD-like airways. Repeated intratracheal administration of PCS to {beta}ENaC-transgenic mice induced airway-centered immune cell accumulation and increased {gamma}{delta} TCR-positive cell accumulation, together with elevated expression of the {gamma}{delta} T-cell-associated cytokines Ifng and Il17a. PCS also increased pulmonary Ccl20 and Ccr6 expression, whereas epithelial alarmin-related genes and M2 macrophage-associated responses were not induced in parallel. In ENaC-overexpressing human airway epithelial cells, PCS induced CCL20 and F2RL1, the gene encoding protease-activated receptor 2 (PAR-2), and reduced the N-terminal PAR-2 signal, consistent with proteolytic receptor cleavage. Direct PAR-2 activation reproduced CCL20 induction, whereas pharmacological PAR-2 inhibition suppressed PCS-induced CCL20 expression. In contrast, PAR-1 inhibition or LPS neutralization with polymyxin B did not suppress this response. These findings support a mucosal epithelial protease-sensing model in which gingipain-containing P. gingivalis products activate PAR-2-dependent CCL20 production in airway epithelial cells and are associated with CCR6-linked {gamma}{delta} T-cell accumulation in COPD-like airways. Contribution to the field statementPeriodontal disease is often associated with chronic obstructive pulmonary disease, but how oral bacterial products affect lung inflammation remains unclear. This study shows that protease-rich products from the periodontal pathogen Porphyromonas gingivalis can be sensed by airway epithelial cells under COPD-like conditions. This response induces a chemokine signal that is linked to the accumulation of {gamma}{delta} T cells, a type of immune cell involved in inflammatory responses. Our findings suggest that the airway epithelium acts as an immune sensor, converting signals from aspirated oral bacterial protease into lung inflammation. This work provides a mechanistic framework for understanding how oral dysbiosis may contribute to immune remodeling in COPD.

immunology↗

bioRxiv2026

Early apelin receptor activation attenuates elastase-induced emphysema and preserves endothelial apelin receptor signaling in mice

Alveolar capillary endothelial cells are positioned adjacent to the alveolar epithelium and contribute to lung homeostasis and injury responses. Single-cell studies have identified aerocyte capillary endothelial cells (aCap), which are specialized for gas exchange, and general capillary endothelial cells (gCap), which contribute to endothelial maintenance and inflammatory signaling. Apelin and its receptor are differentially enriched across these endothelial compartments, but their roles in emphysema development remain incompletely understood. Using an elastase-induced emphysema model in male C57BL/6J mice, we combined bulk RNA sequencing, CIBERSORTx-based cell-type deconvolution, histology, inflammatory assays, pulmonary function testing, and pharmacologic activation of the apelin receptor with [Pyr1]-Apelin-13. At 24 hours after elastase exposure, the inferred fraction of gCap was reduced, and lung expression of apelin and the apelin receptor was decreased. Early [Pyr1]-Apelin-13 administration reduced lung inflammatory mediator expression, Ly6G-positive neutrophil accumulation, bronchoalveolar lavage neutrophil counts, and matrix metalloproteinase-9 activity. Early treatment also attenuated subsequent airspace enlargement, whereas treatment initiated after emphysema was established did not improve physiological or histological outcomes. In a chronic {beta}ENaC-transgenic mouse model, the inferred gCap fraction was maintained, the aCap fraction was reduced, and apelin receptor activation did not improve disease phenotypes. These findings suggest that early activation of the apelin receptor modifies acute inflammatory and endothelium-associated responses following elastase injury and limits emphysematous remodeling in mice. Together, these results support a time-sensitive role for apelin-APJ signaling during the early phase of emphysema development.

molecular biology↗

bioRxiv2026

A hidden thermal mechanism in inhibitory ligand-gated chloride channels

Temperature profoundly shapes neural activity, with temperature-sensitive excitatory cation channels serving as key molecular components of thermosensation and neuronal excitability. Here we show that the glutamate-gated chloride channel AVR-14B, a Cys-loop receptor and principal molecular target of the antiparasitic drug ivermectin in the nematode Brugia malayi, exhibits temperature-dependent gating. Application of glutamate to AVR-14B evoked rapidly desensitizing transient currents; however, above approximately 24 {degrees}C, an additional non-desensitizing sustained current component emerged. Mechanistically, warming altered the gating behavior of the channel, thereby conferring intrinsic temperature sensitivity. Mutational and structural analyses revealed that ions permeate via lateral fenestrations distinct from the central axial pore, forming a noncanonical pathway for temperature-dependent gating. This temperature-dependent gating determines drug efficacy: ivermectin failed to activate AVR-14B below the thermal threshold at which the sustained current emerges. Finally, AVR-14B-null C. elegans showed enhanced heat tolerance, even though wild-type animals generally fail to thrive above 25 {degrees}C, confirming that this molecular mechanism governs organismal physiology. Similar temperature-dependent gating was observed in the human glycine receptor, indicating a conserved principle within this receptor class. Our findings identify inhibitory ligand-gated ion channels as intrinsic thermosensors and uncover a mechanism by which temperature can switch a single receptor between phasic and tonic inhibition, with implications for neural function and temperature-mediated therapeutics.

biophysics↗

bioRxiv2026

Dietary lipids attenuate IGF-1-Akt and injure epithelial-endothelial injury program that accelerates obstructive lung disease

Background Altered lipid metabolism is increasingly implicated in chronic obstructive pulmonary disease (COPD), but it remains unclear how a pre-existing obstructive lung state modifies the response to systemic lipid excess. We investigated whether high-fat diet (HFD) amplifies COPD-relevant lung injury and examined epithelial and vascular programs associated with this response. Methods Male wild-type (WT) and beta-epithelial sodium channel-transgenic ({beta}ENaC-Tg) mice were fed control diet or HFD for 10-11 weeks. Lung structure and function, whole-lung transcriptomes, Akt-FOXO1 signaling, apoptosis-related responses, and pulmonary vascular profiles were assessed. Streptozotocin-induced insulin-deficient diabetes and pharmacological IGF-1 receptor inhibition were used as mechanistic comparators. Palmitate responses were examined in human bronchial epithelial cells, ENaC-hyperactive epithelial cells, and endothelial cells, including conditioned-medium transfer. HFD preconditioning was also evaluated in an elastase-induced emphysema model. Statistical analyses included unpaired two-tailed Student's t tests, one-way ANOVA with Tukey-Kramer or Dunnett multiple-comparison testing, Pearson correlation, and Benjamini-Hochberg correction for RNA-sequencing analyses. Results HFD produced similar increases in body weight, glycemia, and adiposity in WT and {beta}ENaC-Tg mice, while further increasing distal-airspace enlargement and reducing FEV0.1/FVC in {beta}ENaC-Tg mice. Lung transcriptomics revealed coordinated remodeling of lipid metabolic, PI3K-Akt, and vascular programs. HFD reduced Akt phosphorylation, increased FOXO1 and Fasl, and increased TUNEL-positive cells in epithelial regions. Palmitate attenuated IGF-1-induced Akt activation in bronchial epithelial cells, whereas IGF-1 receptor inhibition reproduced Akt suppression and apoptosis-related responses without fully reproducing the HFD phenotype. HFD preconditioning also increased elastase-induced airspace enlargement, accompanied by parallel upregulation of FOXO1 and TUNEL positivity. HFD reduced pulmonary CD34-positive vascular profiles, and palmitate activated endothelial cells directly and through conditioned media from ENaC-hyperactive epithelium. In men with airflow obstruction, hepatic steatosis coincided with lower percent-predicted FEV1. Conclusions Dietary lipid stress amplifies obstructive lung injury and engages complementary epithelial and vascular responses. Impaired epithelial IGF-1-Akt signaling and epithelial-endothelial crosstalk provide a mechanistic framework linking systemic metabolic stress to reduced resilience of the obstructive lung.

molecular biology↗

bioRxiv2026

Left-right asymmetry of the microminipig brain.

Left-right asymmetry of the brain is well recognized in various animals including C. elegans, drosophila and zebrafish. In primates, most of the brain studies describe side of the brain. However, in spite of huge amounts of accumulating rodent studies on neuroscience, most of rodent studies do not distinguish the brain side. The pig brain is considered to occupy an intermediate position between primates and rodents in terms of structural complexity and brain function. Moreover, the numbers of studies using genetic manipulation of pigs are drastically increasing. So, we investigated microminipig (MMP) brain mesoscopic anatomy focusing on left-right differences of its morphology. Here, we show the anterior cingulate cortex, perirhinal cortex, and cerebellum of male and female MMPs, are structurally asymmetrical. The cerebellar vermis, paravermis is tilted from the midline and the consequently the cerebellar cortex exhibits asymmetrical morphology. The anterior cingulate gurus exhibited protrusion and invagination toward the midline on the right and left side, respectively. The left perirhinal lobe exhibited distinct patterns of cortical gyration between left and right side. These data demonstrate that MMPs are one of the suitable model animals for investigating cerebral and cerebellar asymmetry.

neuroscience↗

bioRxiv2025

High-throughput heterospheroid-based screening identifies drugs that reprogram tumor-associated macrophages

The tumor microenvironment (TME) provides a niche for immune evasion and immunotherapy resistance, in part, by recruiting pro-tumor M2-like macrophages. In the present study, using heterospheroids consisting of cancer cells and macrophages, we identified TAM activators, which are compounds that reprogram M2-like tumor-associated macrophages (TAMs) toward the antitumor M1-like phenotype. THP-1- or human peripheral monocyte-derived macrophages were co-cultured with liver cancer cells in an ultra-low attachment dish to generate heterospheroids. Cell surface marker expression and macrophage infiltration into the heterospheroids were assessed by flow cytometry and fluorescence microscopy, respectively. Lipopolysaccharide (LPS) and interferon-{gamma} (IFN{gamma})-induced M1 marker expression was observed on the macrophages in the homospheroids; however, this induction was suppressed in heterospheroids. Microscopic imaging revealed that macrophage infiltration into the heterospheroids was decreased in the presence of LPS and IFN{gamma}, which prompted us to develop a high-content imaging screen. We identified two compounds [alprostadil (prostaglandin E1) and HX531] with TAM-activating activity. RNA-seq analysis revealed that HX531 modulated the immune and IFN response in cancer cells and cell division in macrophages. Moreover, alprostadil promoted the M1-like polarization of TAMs, increased tumor-infiltrating CD8+ T cells, and enhanced anti-PD-1 antibody therapeutic efficacy in a syngeneic mouse xenograft model. In conclusion, the heterospheroid culture recapitulates the immunosuppressive TME, which prevents the M1 polarization of TAMs. It provides a new platform for screening TAM activators and will enable the development of novel cancer immunotherapeutics when combined with high-content imaging analysis.

pharmacology and toxicology↗

bioRxiv2025

RNA Editors Sculpt the Transcriptome During Terminal Erythropoiesis

Selective RNA degradation during terminal erythropoiesis results in a globin-rich transcriptome in mature erythrocytes, but the specific RNA decay pathways remain unknown. We found that deficiency of the terminal uridylyl transferase enzyme Zcchc6 and the 3-5 exoribonuclease Dis3l2 in mouse models led to fetal and perinatal reticulocytosis, an accumulation of RNA-rich precursors of terminal erythroid cells, suggesting their crucial roles in terminal red cell differentiation. Notably, knockout embryos exhibited persistent high-level expression of Hbb-bh1 globin, the ortholog of human fetal{gamma} -globin. Perturbation of the Zcchc6-Dis3l2 pathway in mice engineered to express the human {beta}-globin locus likewise increased{gamma} -globin levels in fetal erythroid cells, suggesting that globin switching entails post-transcriptional mechanisms of mRNA destabilization in addition to transcriptional down-regulation. We cultured human hematopoietic stem and progenitor cells (HSPCs), performed CRISPR/Cas9-mediated knockout of ZCCHC6 and DIS3L2, and observed accumulation of RNA and elevated {gamma}-globin levels in terminal erythroid cells. Our findings reveal a conserved role for the ZCCHC6/DIS3L2 RNA editors in terminal erythropoiesis and demonstrate a post-transcriptional mechanism for{gamma} -globin gene switching, advancing research into in vitro erythrocyte generation and{gamma} -globin stabilization to ameliorate hemoglobinopathies.

developmental biology↗

bioRxiv2024

Structural Insights into the DNA-Binding Mechanism of BCL11A: The Integral Role of ZnF6

The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: 2{gamma}2) to adult hemoglobin (HbA: 2{beta}2) during development. BCL11A binds at a cognate recognition site (TGACCA) in the {gamma}-globin gene promoter and represses its expression. DNA-binding is mediated by a triple zinc finger domain, designated ZnF456. Here, we report comprehensive investigation of ZnF456, leveraging X-ray crystallography and NMR to determine the structures in both the presence and absence of DNA. We delve into the dynamics and mode of interaction with DNA. Moreover, we discovered that the last zinc finger of BCL11A (ZnF6) plays a special role in DNA binding and {gamma}-globin gene repression. Our findings help account for some rare {gamma}-globin gene promoter mutations that perturb BCL11A binding and lead to increased HbF in adults (hereditary persistence of fetal hemoglobin). Comprehending the DNA binding mechanism of BCL11A opens avenues for the strategic, structure-based design of novel therapeutics targeting sickle cell disease and {beta}-thalassemia.

molecular biology↗

bioRxiv2023

Isolation of stage-specific spermatogenic cells by dynamic histone incorporation and removal in spermatogenesis.

Due to the lack of an in vitro spermatogenesis system, studies on mammalian spermatogenesis require the isolation of specific germ cell populations for further analyses. BSA gradient and elutriation have been used for several decades to purify testicular germ cells; more recently, fluorescence-activated cell sorting (FACS) has become popular. Although each method has its advantages and disadvantages and is used depending on the purpose of the experiment, reliance on FACS is expected to be more prevalent because fewer cells can be managed. However, the currently used FACS method for testicular germ cells relies on karyotypic differences via DNA staining. Thus, it remains challenging to separate post-meiotic haploid cells (spermatids) according to their differentiation stage despite significant variations in morphology and chromatin state. In this study, we developed a method for finely separating testicular germ cells using VC mice carrying fluorescently tagged histones. This method enables the separation of spermatogonia, spermatocytes, and spermatids based on the intensity of histone fluorescence and cell size. Combined with a DNA staining dye, this method separates spermatids after elongation according to each spermiogenic stage. Although the necessity for a specific transgenic mouse line is less versatile, this method is expected to be helpful for the isolation of testicular germ cell populations because it is highly reproducible and independent of complex cell sorter settings and staining conditions.

developmental biology↗

bioRxiv2023

A novel mouse allele of the DNA/RNA helicase senataxin (Setxspcar3) causing meiotic arrest of spermatocytes and male infertility

An unbiased screen for discovering novel genes for fertility identified the spcar3, spermatocyte arrest 3, mutant phenotype. The spcar3 mutation identified a new allele of the Setx gene, encoding senataxin, a DNA/RNA helicase that regulates transcription termination by resolving DNA/RNA hybrid R-loop structures. Although mutations in the human SETX gene cause neural disorders, Setxspcar3 mutant mice do not show any apparent neural phenotype, but instead exhibit male infertility and female subfertility. Histology of the Setxspcar3mutant testes revealed absence of spermatids and mature spermatozoa in the seminiferous tubules. Cytological analysis of chromosome spread preparations of the Setxspcar3 mutant spermatocytes revealed normal synapsis, but aberrant DNA damage in the autosomes, and defective formation of the sex body. Furthermore, Setxspcar3 testicular cells exhibited abnormal accumulation of R-loops compared to wild type testicular cells. Transient expression assays identified regions of the senataxin protein required for sub-nuclear localization. Together, these results not only confirm that senataxin is required for normal meiosis and spermatogenesis but also provide a new resource for determination of its role in maintaining R-loop formation and genome integrity.

cell biology↗

bioRxiv2023

Structure, signals, and cellular elements of the mouse gastric mesenchymal niche

PDGFRA-expressing mesenchyme provides a niche for intestinal stem cells. Corresponding compartments are unknown in the stomach, where corpus and antral glandular epithelia have similar niche dependencies but are structurally distinct from the intestine and from each other. Previous studies considered antrum and corpus as a whole and did not assess niche functions. Using high-resolution imaging and sequencing, we identify regional subpopulations and niche properties of purified mouse corpus and antral PDGFRA+ cells. PDGFRAHi sub-epithelial myofibroblasts are principal sources of BMP ligands in both gastric segments; two molecularly distinct groups distribute asymmetrically along antral glands but together fail to support epithelial organoids in vitro. In contrast, strategically positioned PDGFRALo cells that express CD55 enable corpus and antral organoid growth in the absence of other cellular or soluble factors. Our study provides detailed insights into spatial, molecular, and functional organization of gastric mesenchyme and the spectrum of signaling sources for stem cell support.

cell biology↗

bioRxiv2022

Actin filaments accumulate in the nucleus during interphase and remain in the vicinity of condensing chromosomes during prophase to metaphase in zebrafish early embryos

In the cytoplasm, filamentous actin (F-actin) plays a critical role in cell regulation, including cell migration, stress fiber formation, and cytokinesis. Recent studies have shown that actin filaments that form in the nucleus are associated with diverse functions. Here, using live imaging of an F-actin-specific probe, superfolder GFP-tagged utrophin (UtrCH-sfGFP), we demonstrated the dynamics of nuclear actin in zebrafish (Danio rerio) embryos. In early zebrafish embryos up to around the high stage, UtrCH-sfGFP increasingly accumulated in nuclei during the interphase and reached a peak during the prophase. After nuclear envelope breakdown (NEBD), patches of UtrCH-sfGFP remained in the vicinity of condensing chromosomes during the prometaphase to metaphase. When zygotic transcription was inhibited by injecting -amanitin, the nuclear accumulation of UtrCH-sfGFP was still observed at the sphere and dome stages, suggesting that zygotic transcription may induce a decrease in nuclear F-actin. The accumulation of F-actin in nuclei may contribute to proper mitotic progression of large cells with rapid cell cycles in zebrafish early embryos, by assisting in NEBD, chromosome congression, and/or spindle assembly. Summary statementFilamentous actin accumulates in the nucleus of zebrafish early embryos and forms patches associating with condensing chromosomes during prophase.

cell biology↗

bioRxiv2022

Inhibition of the BMP pathway suppresses tumor growth via downregulation of EGFR in MEK/ERK-dependent colorectal cancer

The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, the effect of the BMP pathway in colorectal cancer (CRC) is controversial; it can either be tumor promoting or tumor suppressing, depending on the study. In this study, we found that CRC cells reside in a BMP-rich environment based on RNA-sequencing database analysis. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of organoids in some CRC cases. CRC organoids treated with LDN193189 exhibited a decrease in epidermal growth factor receptor, which was, at least in part, mediated by protein degradation induced by leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1). Among CRC organoid panels from 18 different patients, suppression of organoid growth by BMP inhibition correlated with the induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth-suppressive effect of LDN193189. Furthermore, simultaneous treatment with LDN192189 and trametinib, an FDA-approved MEK inhibitor, resulted in a combination effect in both in vivo and in vitro xenograft tumor treatment in CRC organoids, which are susceptible to growth suppression by LDN193189. Taken together, the simultaneous inhibition of BMP and MEK can be a novel treatment option in CRC cases, and evaluating in vitro growth suppression and LRIG1 induction by BMP inhibition using patient-derived organoids could offer functional biomarkers for predicting potential responders.

cancer biology↗

bioRxiv2021

Production of offspring from azoospermic mice with meiotic failure: Precise biparental meiosis within halved oocytes

While the large volume of mammalian oocytes is necessary for embryo development, it can lead to error-prone chromosomal segregation during meiosis. Conversely, we hypothesized that smaller oocytes would have a great unidentified potential to stabilize unstable meiosis and improve the development of the resultant embryos. Here, we show that reducing ooplasmic volume can rescue highly error-prone fertilization using primary spermatocytes by preventing segregation errors of chromosomes during biparental meiosis. High-resolution live-imaging analysis revealed that erroneous chromosome segregation occurred in most (90%) spermatocyte-injected oocytes of normal size, but could be ameliorated to 40% in halved oocytes. The birth rate improved remarkably from 1% to 19% (P < 0.0001). Importantly, this technique enabled the production of offspring from azoospermic mice with spermatocyte arrest caused by STX2 deficiency, an azoospermia factor also found in humans. Thus, contrary to popular opinion, oocytes inherently have a strong potential for precise meiotic divisions, which can be evoked by reduction of the ooplasmic volume. Their potential might help rescue cases of untreatable human azoospermia with spermatocyte arrest.

developmental biology↗

bioRxiv2021

Preparation of "stress-free" concanavalin A-conjugated Dynabeads magnetic beads for CUT&Tag

Epigenome research has employed various methods to identify genomic location of proteins of interest, such as transcription factors and histone modifications. A recently established method called CUT&Tag uses a Protein-A Tn5 transposase fusion protein, which cuts the genome and inserts adapter sequences nearby the target protein. Throughout most of the CUT&Tag procedure, cells are held on concanavalin A (con A)-conjugated magnetic beads. Proper holding of cells would be decisive for the accessibility of Tn5 to the chromatin, and efficacy of the procedure of washing cells. However, BioMag(R)Plus ConA magnetic beads, used in the original CUT&Tag protocol, often exhibit poor suspendability and severe aggregation. Here, we compared the BioMag beads and Dynabeads(R) magnetic particles of which conjugation of con A was done by our hands, and examined the performance of these magnetic beads in CUT&Tag. Among tested, one of the Dynabeads, MyOne-T1, kept excessive suspendability in a buffer even after overnight incubation. Furthermore, the MyOne-T1 beads notably improved the sensitivity in CUT&Tag assay for H3K4me3. In conclusion, the arrangement and the selection of MyOne-T1 refine the suspendability of beads, which improves the association of chromatin with Tn5, which enhances the sensitivity in CUT&Tag assay.

bioinformatics↗

bioRxiv2020

Schizophrenia and autism-associated mutations and disrupted m6A signal by YTHDF1 cause defects in microtubule function and neurodevelopment

Subcellular mRNA localization and local translation are crucial for spatially regulated gene expression in neurons. However, the precise mechanisms governing the selective transport and translation of mRNAs contributing to processes such as axonal growth and branching are only partially understood. Here, we present evidence of N6-methyladenosine (m6A)-mediated translational control of the RNA-binding protein, APC, influencing cytoskeletal dynamics at the growth cone. Our findings demonstrate that m6A modifications occur on Apc mRNA, facilitating its recognition by YTHDF1 to promote APC translation in neuronal somata. Additionally, we observe that disrupting the m6A pathway impairs the transport and local translation of {beta}-actin mRNA in the axon and growth cones, a deficiency that can be rescued by the exogenous expression of APC protein in cultured neurons. Furthermore, we establish the essential role of YTHDF1 in axon development, particularly in callosal projection neurons during cortical development. Our findings suggest a novel mechanism involving m6A-mediated regulation of APC protein translation, linking epitranscriptomics to axonal mRNA targeting, cytoskeletal dynamics, and axon development.

neuroscience↗

bioRxiv2020

Direct uptake mechanism in lysosome required for neuromuscular homeostasis

The degradation of cellular components plays an essential role in homeostasis. However, the known degradation pathways cannot account for the levels of proteolysis in cells. Here, we demonstrate that cytosolic proteins are imported into lysosomes in an ATP-dependent manner for degradation through a direct uptake mechanism distinct from any known pathway. SIDT2, a lysosomal membrane protein previously reported as an RNA transporter, translocates substrate proteins across the lysosomal membrane. Furthermore, we identify a dominant-negative mutation in SIDT2 that causes neuropathy and distal myopathy with rimmed vacuoles, a protein aggregation disease in humans. We generate Sidt2 knockout mice, recapitulating the characteristic features of this disease. Our results reveal a novel degradation pathway and illustrate its crucial role in cellular proteostasis, physiology, and pathophysiology. One Sentence SummaryDiscovery of a novel proteolytic pathway in cells, the dysfunction of which leads to protein aggregation disease in humans.

cell biology↗