Bode, H. | Search bioRxiv

bioRxiv2025

The VelB intrinsically disordered domain promotes selective heterodimer formation of velvet domain regulatory proteins for fungal development

Fungi possess several transcription factors with a characteristic velvet domain for DNA-binding and homo- or heterodimerization, which is structurally similar to the mammalian NF-B Rel homology domain. Velvet dimers control fungal development, virulence and mycotoxin formation. VelB is the only regulator, which carries an intrinsically disordered domain (IDD) within the velvet domain. The IDD as well as the positioning within VelB is conserved in the fungal kingdom. Intrinsically disordered regions contribute to transcription activation and DNA binding and frequently appear in eukaryotic transcription factors. The VelB IDD provides selective heterodimerization as well as protein stability control. The IDD is not required for the formation of the VelB-VeA heterodimer of Aspergillus nidulans or Verticillium dahliae, but promotes the formation of the VelB-VosA heterodimer. The IDD destabilizes VelB single molecules and also balances its distribution and ratio between both velvet heterodimers. These balances contribute to control appropriate mycotoxin production and sexual development. Herewith, the VelB IDD represents a novel control mechanism of velvet protein stability and heterodimer formation for precise priming of fungal development.

molecular biology↗

bioRxiv2023

Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability

Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.

neuroscience↗

bioRxiv2019

An insect serotonin receptor mediates cellular immune responses and its inhibition by phenylethylamide derivatives from bacterial secondary metabolites

Serotonin (5-hydroxytryptamine: 5-HT) is a biogenic monoamine that mediates immune responses and modulates nerve signal in insects. Se-5HTR, a specific receptor of serotonin, has been identified in the beet armyworm, Spodoptera exigua. It is classified into subtype 7 among known 5HTRs. Se-5HTR was expressed in all developmental stages of S. exigua. It was expressed in all tested tissues of larval stage. Its expression was up-regulated in hemocytes and fat body in response to immune challenge. RNA interference (RNAi) of Se-5HTR exhibited significant immunosuppression by preventing cellular immune responses such as phagocytosis and nodulation. Treatment with an inhibitor (SB-269970) specific to 5HTR subtype 7 resulted in significant immunosuppression. Such immunosuppression was also induced by bacterial secondary metabolites derived from Xenorhabdus and Photorhabdus. To determine specific bacterial metabolites inhibiting Se-5HTR, this study screened 37 bacterial secondary metabolites with respect to cellular immune responses associated with Se-5HTR and selected 10 potent inhibitors. These 10 selected compounds competitively inhibited cellular immune responses against 5-HT and shared phenylethylamide (PEA) chemical skeleton. Subsequently, 46 PEA derivatives were screened and resulting potent chemicals were used to design a compound to be highly inhibitory against Se-5HTR. The designed compound was chemically synthesized. It showed high immunosuppressive activities along with specific and competitive inhibition activity for Se-5HTR. This study reports the first 5HT receptor from S. exigua and provides its specific inhibitor designed from bacterial metabolites and their derivatives. Author SummarySerotonin (5-hydroxytryptamine: 5-HT) plays a crucial role in mediating nerve and immune signals in insects. Interruption of 5-HT signal leads to malfunctioning of various insect physiological processes. Se-5HTR, a 5-HT receptor of beet armyworm, Spodoptera exigua, was identified and classified as subtype 7 (5-HT7) of 5-HT receptors. A specific inhibitor (SB-269970) for 5-HT7 highly inhibited immune responses such as phagocytosis and nodulation mediated by Se-5HTR. Two entomopathogenic bacteria, Xenorhabdus and Photorhabdus, could secrete potent inhibitors against immune responses mediated by 5-HTR. Bacterial secondary metabolites were screened against Se-5HTR-mediating immune responses. Most of resulting compounds shared phenylethylamide (PEA) chemical skeleton. Subsequent screening using PEA derivatives supported the importance of this chemical skeleton. Based on their relative inhibitory activities, a compound was designed and synthesized. This novel compound possessed high inhibitory activities against Se-5HTR-mediating immune responses and exhibited competitive inhibition with 5-HT.

immunology↗