Communications Biology最新文献

The G protein-coupled receptor associated sorting protein 2 (GPRASP2) gene mutation is one of only three deafness genes identified to be implicated in X-linked recessive syndromic hearing loss (SHL) to date. However, the function of GPRASP2 in the auditory system has not yet been fully understood. In this study, we generated Gprasp2-deficient mice and found that they exhibited a hearing loss phenotype and depression-like behaviors. In addition, we observed a disordered arrangement of cochlear hair cells in Gprasp2-deficient mice. GPRASP2 binds to NCAM1. Gprasp2 deficiency decreased NCAM1 level and further enhanced ferritinophagy in cochlear hair cells. This study could improve our understanding of the role of GPRASP2 deficiency in auditory cells, which contributes to the pathophysiology of X-linked SHL.

WhiB-like (Wbl) family proteins are a unique family of iron-sulfur ([4Fe-4S]) cluster-bound transcription factors found exclusively in Actinobacteria and actinobacteriophages, including the notoriously persistent pathogen Mycobacterium tuberculosis (Mtb). Despite their critical roles in cell development, stress response and antibiotic resistance, the mechanisms of gene regulation by the Wbl family proteins are not fully understood due to the lack of a canonical DNA-binding motif in most Wbl proteins. Here, we present structural and biochemical evidence demonstrating that all Mtb Wbl proteins bind to the same site in the conserved region 4 of the primary sigma 70 factor facilitated by a previously unrecognized structural motif, the aromatic patch, in the Wbl family. Our phylogenetic findings provide compelling evidence for a complex evolutionary relationship of Wbls between actinobacteria and the associated phages. Together, this work fills a critical gap in our understanding of the function, mechanism and evolutionary origin of Wbls.

Although recent studies have suggested that the Omicron strain is less severe, the prevalence of long Omicron variants and their subvariant waves continues today. Here, we analyze the pathological characteristics of SARS-CoV-2 variants in cynomolgus macaques. Prolonged re-challenge analysis results in the establishment of re-infection in some macaques with both the same strain and different strains. Omicron infection shows low pathogenicity; however, all macaques that developed pneumonia were inoculated with Omicron strains at the second inoculation. Interestingly, antibodies against the Wuhan, Alpha, and Delta strains are strongly induced regardless of the strain, but antibodies against Omicron strains are not. Moreover, despite the re-infection strain, antibody levels against the Wuhan strain are highest, suggesting original antigenic sin. In addition, Omicron infection induces weaker antigen-specific T-cell responses. These results indicate that immune responses to viral infection differ between the variants, and these differences could inform vaccine development strategies.

Understanding the network topology of a cluster of diverse neurons acting in concert requires a detailed expression map of ligand-receptor pairs involved in cell-cell communication. The neuropeptide arginine vasopressin (AVP) and signaling mediated by its cognate receptor V1a have been implicated in dorsal-to-ventral regional communication in the suprachiasmatic nucleus (SCN), a cluster of neurons that acts in concert to generate daily rhythms in behavior and physiology. Here, we show that among vasoactive intestinal peptide (VIP)-ergic neurons in the ventral SCN only a small subpopulation expresses V1a, and we demonstrate the requirement of V1a in these VIP neurons for maintaining the robustness of the circadian clock using a jet-lag paradigm. Notably, we found that V1a expression appears to be minimal in the other major ventral neuronal population expressing gastrin-releasing peptide (GRP). The identified heterogeneity between VIP and GRP neurons, and among VIP neurons, provides a basic map for understanding the cryptic network structure from dorsal AVP neurons to receiver ventral SCN.

Tuberculosis, especially drug-resistant tuberculosis remains a global threat, and new drugs are desperately needed to combat the spread of multidrug-resistant Mycobacterium tuberculosis. Here we describe a natural macrotetrolide dinactin with anti-tuberculosis activity against susceptive and non-replicating Mycobacterium tuberculosis. Dinactin can also synergistically enhance the anti-tuberculosis effect of rifampicin and isoniazid against drug-resistant strains.Furthermore, dinactin exhibited excellently antituberculosis effect in macrophage and Galleria mellonella models. Since the ionophore properties of dinactin, it not only enhanced cations transport and altered membrane permeability but also caused the dissipation of proton motive force and metabolic perturbations. Finally, through the selection of spontaneous resistant mutants and whole genome sequencing, non-synonymous single nucleotide polymorphisms were successfully identified in the cpsA gene of the LytR-Cps2A-Psr family. The dinactin-resistant mutants exhibited decreased in vitro drug sensitivity to dinactin without cross-resistance to first-line antituberculosis drugs. Genetic studies and molecular biology assays have subsequently confirmed cpsA as one of the potential targets for dinactin's anti-tuberculosis activity. Collectively, these data indicate that dinactin could be a promising candidate for treating tuberculosis.

L1s are repetitive sequences capable of copying themselves into new genomic loci. While L1s are typically repressed by DNA methylation in somatic tissues, they can become reactivated in cancer. Although L1 sequences are highly repetitive, ~25% of insertions carry a unique downstream sequence, transduction, that can be used to trace the source L1. Here, we apply nanopore long-read sequencing to 56 colorectal cancer samples to comprehensively detect somatic transductions and to characterize the source L1 activity. We demonstrate that earlier methods systematically miss a large proportion of mostly shorter transductions, leading to an incomplete and biased view of source L1 activity. Our analysis reveals a strong positive correlation between the number of transductions and other L1 insertions within samples and that distinct source L1s exhibit varying transduction lengths and 5' inversion frequency. Finally, we integrate DNA methylation provided by nanopore reads and show that active elements in cancer samples have lower methylation levels in contrast to inactive L1s. Together, our results provide a more complete characterization of somatically active L1 elements in colorectal cancer and highlight the utility of long-read sequencing in retrotransposon research.

Interferon regulatory factors (IRFs) are essential for transcription of interferons (IFNs), interferon-stimulated genes (ISGs), and pro-inflammatory cytokines. We profile the transcriptome of human monocyte THP1 cells challenged with cGAMP, LPS, or IFNB1 protein as a function of knockout (KO) or overexpression (OE) of IRFs or KO of IFNAR2. We define distinct gene expression groups, reflecting the transcription factors responsible for their induction including subgroups activated by more than one pathway or feed-forward regulation. We compare IRF3- and IRF7-induced gene signatures and note the strong direct induction of a subset of antiviral-acting ISGs by IRF3 or IRF7. LPS treatment induces NF-κB responses in monocyte and macrophage state cells, however, IFNs and ISGs are only co-induced in the macrophage state requiring IRF3. IRF1, IRF2, IRF5, and IRF8 are largely dispensable for IFN-stimulated or innate-immune-mediated gene induction. This study provides a valuable resource for dissecting complex inflammatory gene signatures and their underlying transcription factors thereby anticipating the effects of selectively drugging the underlying pathways.

Human cytomegalovirus (HCMV) encodes the orphan G protein-coupled receptor (GPCR) UL33, which exhibits constitutive activity that disrupts host G protein signalling, facilitating efficient viral replication and pathogenesis. The cryo-electron microscopy (cryo-EM) structure of UL33 bound to the G_s subtype of G protein reveals the N-terminal peptide as a tethered ligand reminiscent of the protease-activated receptors and adhesion GPCRs. This self-agonism induces a non-canonical active state that facilitates promiscuous G protein coupling, a plausible viral strategy for fine-tuning host signalling. Structure-guided mutagenesis disrupting key interactions between the N-terminus and its binding pocket abolishes G protein-mediated signalling, confirming the role of the N-terminus as a self-agonist. Our findings elucidate the structural basis for this activation mechanism and highlight the strategies employed by HCMV to hijack host G protein signalling.

The hippocampus plays a crucial role in cognition, yet its microstructural development during childhood and adolescence remains poorly understood. Here, we investigate age-related differences in hippocampal microstructure using diffusion MRI with ultra-strong gradients (300 mT/m) in a cohort of 88 participants aged 8-19 years. Surface-based hippocampal modelling was combined with established microstructural approaches, and a more advanced biophysical model (Soma and Neurite Density Imaging: SANDI) suited for studying cortical microstructure. Hippocampal volume, gyrification, and thickness remained stable across this developmental window, however we observed significant differences across age related to MR-derived neurite and soma parameters. Diffusion-derived changes across age were found to be correlated with adult microstructure maps related to myelin and iron content, synaptic density, and hippocampal interneurons derived from MRI, PET and histology. These findings highlight age-related differences of MR-derived neurite and soma parameters in the human hippocampus during late childhood and adolescence, offering insights into structural maturation during this critical period.

Kainate receptors (KARs), a distinct subfamily of ionotropic glutamate receptors, are critical modulators of synaptic transmission and network excitability. Their function is intricately regulated by auxiliary subunits and endogenous ions. The GluK3 subunit, in particular, exhibits unique gating and modulatory properties; however, the interplay between its known regulators, the Neto auxiliary proteins, and synaptic zinc remains poorly understood. We reveal a multi-layered regulatory system governing the function of GluK3. Using whole-cell electrophysiology, we demonstrate that the auxiliary subunits Neto1 and Neto2 differentially regulate the gating kinetics of GluK3. While both proteins markedly slow receptor desensitization and relieve the intrinsic polyamine block, they exert opposing effects on the rate of recovery from desensitization, with Neto1 accelerating and Neto2 decelerating recovery, suggesting distinct mechanisms for tuning synaptic fidelity. Crucially, we show that Neto proteins uniquely reshape the potentiation of GluK3 currents by zinc. Neto2, in particular, acts synergistically with zinc to produce a profound facilitation of peak currents. To dissect these regulatory pathways, we utilized a GluK3 (D759G) mutant, which ablates the LBD dimer interface zinc-binding site. This mutation unmasked a secondary, inhibitory zinc-binding site, revealing a previously unknown layer of modulation. While the (D759G) mutant preserved the fundamental modulatory actions of Neto proteins, the Neto isoforms differentially regulated this previously unidentified revealed inhibitory zinc effect. Cryo-electron microscopy confirms that the (D759G) mutation promotes a more compact arrangement of the ligand-binding domain (LBD), consistent with its stabilizing effect on gating. Together, these findings establish a distinct framework for understanding KAR function, where auxiliary subunits and ionic modulators converge to create a highly tunable signaling complex essential for synaptic plasticity.