Biology subjects

Watari, H.

Publications and source records attributed to Watari, H..

4 recordsLinked to original sources

bioRxiv2025

Modulation of translational elongation by montanine alkaloids preferentially inhibits RNA viruses

Montanine, an Amaryllidaceae alkaloid, has demonstrated superior antiviral activity against dengue virus (DENV), SARS-CoV-2, vesicular stomatitis Indiana virus (VSV-G), and vesicular stomatitis virus pseudotyped with Ebola virus glycoprotein (VSV-ZGP), outperforming other antiviral alkaloids tested, including lycorine, narciclasine, tetracetylnarciclasine, and pancracine. We further showed that montanine inhibits translation in mammalian cells, as evidenced by a puromycin incorporation assay. Cryo-EM analysis revealed that montanine binds to the peptidyl transferase center of the human ribosome. A chemical genomics survey indicated that the knockdown of the GCN1 complex, which senses ribosome collisions and triggers the translation quality control process, increased the cytotoxicity of montanine while reducing viral infectivity. Together, these results suggest that the antiviral activity of montanine is closely linked to its impact on translational elongation and GCN1-related stress responses, underscoring the potential of translation control as a targeted mode for RNA virus therapeutics. Significance StatementMontanine, an alkaloid from the Amaryllidaceae family known for its diverse bioactivities, was identified as a potent antiviral compound from a library of natural plant- and fungus-derived substances. Through a combination of biochemical assays and cryo-EM analysis, we discovered that montanine binds to the peptidyl transfer center of the human ribosome, effectively inhibiting protein synthesis. Based on these findings and a chemical genomics approach, we hypothesize that the translational control of montanine triggers a cellular response that impedes viral replication. We propose that molecules capable of modulating translation efficacy could serve as unique lead compounds in the development of broad-spectrum antiviral agents.

biochemistry↗

bioRxiv2022

The developmental origin and the specification of the adrenal cortex in humans and cynomolgus monkeys

Development of the adrenal cortex, a vital endocrine organ, originates in the adrenogonadal primordium, a common progenitor for both the adrenocortical and gonadal lineages in rodents. In contrast, we find that in humans and cynomolgus monkeys, the adrenocortical lineage originates in a temporally and spatially distinct fashion from the gonadal lineage, arising earlier and more anteriorly within the coelomic epithelium. The adrenal primordium arises from adrenogenic coelomic epithelium via an epithelial-to- mesenchymal-like transition, which then progresses into the steroidogenic fetal zone via both direct and indirect routes. Notably, we find that adrenocortical and gonadal lineages exhibit distinct HOX codes, suggesting distinct anterior-posterior regionalization. Together, our assessment of the early divergence of these lineages provides a molecular framework for understanding human adrenal and gonadal disorders. One Sentence SummarySpecification of the adrenal cortex occurs in adrenogenic coelomic epithelium independent of gonadogenesis in humans and cynomolgus monkeys

developmental biology↗

bioRxiv2021

Hidden pathway for cytokine receptor activation: Structural insights into a marine sponge-derived lectin that activates the thrombopoietin receptor via recognition of the fucose moiety

N-glycan-mediated activation of the thrombopoietin receptor (MPL) under pathological conditions has been implicated in myeloproliferative neoplasms induced by mutant calreticulin, which forms an endogenous receptor-agonist complex that constitutively activates the receptor. However, the molecular basis for this mechanism has not been studied because no external agonists existed. We describe the structure and function of a marine sponge-derived MPL agonist, thrombocorticin (ThC), a homodimerized lectin with calcium-dependent fucose-binding properties. ThC-induced activation persists due to limited receptor internalization. The strong synergy between ThC and thrombopoietin suggests that ThC catalyzes the formation of receptor dimers on the cell surface. MPL is subject to sugar-mediated activation, where the kinetics differ from those of cytokines. This result suggests the presence of diverse receptor activation pathways in human thrombopoiesis. One-sentence summaryA marine sponge lectin catalyzes thrombopoietin receptor dimerization and activation, exhibiting strong synergy with thrombopoietin, and modulates internalization of the receptor.

cell biology↗

bioRxiv2020

Navigating the translational roadblock: Towards highly specific and effective all-optical interrogations of neural circuits

Two-photon (2-P) all-optical approaches combine in vivo 2-P calcium imaging and 2-P optogenetic modulations and have the potential to build a framework for network-based therapies, e.g. for rebalancing maladaptive activity patterns in preclinical models of neurological disorders. Here, our goal was to tailor these approaches for this purpose: Firstly, we combined in vivo juxtacellular recordings and GCaMP6f-based 2-P calcium imaging in layer II/III of mouse visual cortex to tune our detection algorithm towards a 100 % specific identification of AP-related calcium transients. False-positive-free detection was achieved at a sensitivity of approximately 73 %. To further increase specificity, secondly, we minimized photostimulation artifacts as a potential source for false-positives by using extended-wavelength-spectrum laser sources for optogenetic stimulation of the excitatory opsin C1V1. We achieved artifact-free all-optical experiments performing photostimulations at 1100 nm or higher and simultaneous calcium imaging at 920 nm in mouse visual cortex in vivo. Thirdly, we determined the spectral range for maximizing efficacy of optogenetic control by performing 2-P photostimulations of individual neurons with wavelengths up to 1300 nm. The rate of evoked transients in GCaMP6f/C1V1-co-expressing cortical neurons peaked already at 1100 nm. By refining spike detection and defining 1100 nm as the optimal wavelength for artifact-free and effective stimulations of C1V1 in GCaMP-based all-optical interrogations, we increased the translational value of these approaches, e.g. for the use in preclinical applications of network-based therapies. One Sentence SummaryWe maximize translational relevance of 2-P all-optical physiology by increasing specificity, minimizing artifacts and optimizing stimulation efficacy.

neuroscience↗