Communications Biology最新文献

Early animal embryos must balance the efficiency with the accuracy of mitotic control. However, the extent of mitotic errors that can be safely endured at different stages of development is unclear. In this study, using a recently developed photoswitchable CENP-E inhibitor, we introduce transient mitotic errors at various developmental windows and systematically address their organismal effects. Upon CENP-E inhibition in the pre-gastrula period, embryos suffer gradual aggravation of developmental defects as the duration of the inhibition extends. Conversely, embryos tolerate several hours of consecutive CENP-E inhibition in the gastrula period, frequently achieving full development. Live imaging reveals that chromosome misalignment caused by CENP-E inhibition results in a modest mitotic delay in the gastrula, but not in the early pre-gastrula period, suggesting the gradual functionalization of the spindle assembly checkpoint (SAC) at this stage. This mitotic delay helps alleviate, though not perfectly resolve, polar chromosome misalignment before anaphase onset. Importantly, pharmacological suppression of SAC renders gastrula embryos inviable upon CENP-E inhibition. Therefore, despite its leaky nature, the embryonic SAC contributes to partial mitotic error correction, which proves essential to manage consecutive mitotic perturbations. Our results demonstrate the power of optochemical approaches in understanding the robust control of dynamic processes in development.

The SINE-encoded B2 retrotransposon is an RNA Polymerase III (POL-III)-derived transcript whose expression is substantially upregulated during various cellular stress responses. Beyond retrotransposition, the B2 non-coding RNA can directly bind and repress the activity of RNA Polymerase II (POL-II), leading to a significant downregulation of transcripts during stress. Notably, our recent findings have shown that B2 is a self-cleaving ribozyme whose activity can be induced by interactions with chromatin-modifying factors through non-canonical epigenetic mechanisms that co-regulate its function across distinct chromatin-binding target loci. Here, by integrating RNA chemical probing, small-angle X-ray scattering, and 3D motif modeling, we determine structural ensemble-to-function relations for the B2 SINE ribozyme RNA. Genetic perturbations of the RNA suggest that the B2 SINE ribozyme has a well-defined secondary and dynamic tertiary structure that depends on the integrity of the critical region, which confers ribozymatic activity and repressive extent by POL-II. Using an RNA engineering approach, we examine the effects of point mutations, deletions of the main cleavage site, and deletions of the cleavage domain on the structural ensemble of the RNA. Combining this approach with in vitro and in vivo functional perturbation methods highlights the relationships between structural ensembles and various biologically relevant functional outcomes.

A head region with specialised appendages, sclerotization, and segmentation of the trunk (arthrodization), and its appendages (arthropodization) represent three key innovations in arthropod evolution. Two scenarios have been proposed for acquisition of these innovations either in a synchronous or a sequential mode. Here we describe a new species Sunella dimorphismus sp. nov., from the Chengjiang biota (ca. 518 Ma), which displays a bivalved carapace, raptorial frontal appendages, and an arthrodized trunk with a series of biramous arthropodized appendages revealed by new specimens and new observations with assistance of computed tomography. Phylogenetic analyses placed Sunella as the earliest diverging deuteropods besides Erratus. Ancestral state reconstructions refine our understanding of the gain and loss of key characters in the euarthropod. The results demonstrate that trunk limb arthropodization preceded trunk arthrodization, with both prior to the evolution of a six-segmented functional head, while the trunk arthrodization is found to be lost in isoxyiids.

In mammals, circadian entrainment relies on signaling pathways that translate light input into molecular changes within the central pacemaker, the suprachiasmatic nucleus (SCN). Here, using β‑arrestin1 (ARRB1)-deficient mice, we identify a critical role for β‑arrestin1 in this process, showing that endosomal signaling underlies key steps in clock resetting. We demonstrate that ARRB1 is required for PAC1 receptor internalization and for the activation of endosomal signaling in response to light or PACAP. ARRB1‑dependent PAC1 endosomal signaling activates an ERK1/2-RSK1-S6 cascade that enhances protein translation and contributes to the induction of PER proteins. Transcriptional responses remain intact, underscoring the spatial specificity of ARRB1 function. Our findings position endosomes as critical subcellular hubs for circadian signal transduction and reveal a non-canonical, β-arrestin1-dependent entrainment mechanism that operates through translational control. Together, these results challenge traditional GPCR signaling paradigms and establish endosome-based signaling as a key regulator of circadian timekeeping.

Ferritins are ubiquitous among life forms, as they are essential for iron homeostasis. Here, we unveiled a novel member of the ferritin family, baptised mini-bacterioferritin. The characterised mini-bacterioferritin was isolated from a microbial enrichment dominated by the methanotrophic archaeon 'Candidatus Methanoperedens carboxydivorans'. Its atomic resolution crystal structure reveals a 12-mer assembly with a diiron ferroxidase centre located within a four-helix bundle. Redox-cycling experiments on protein crystals reveal a shift in iron position at the active site, which follows the established ferritin catalytic cycle. The 12-mer sphere-like structure harboured six Fe-coproporphyrin III ligands, positioned at the interdimeric interface, a characteristic previously only found in 24-mer bacterioferritins. Phylogenetics, together with structure predictions of closely related proteins, revealed that mini-bacterioferritins form a distinct clade within the ferritin family that might conserve ancestral traits. Future research will need to investigate the physiological roles of these enzymes, which were unsuspectingly widely distributed among prokaryotes.

Stress elicits variable systemic and neural changes, with outcomes ranging from adaptive to pathological. Several studies have implicated the dorsal raphe nucleus (DRN), a brainstem nucleus containing a heterogeneous population of serotonergic (5-HT) neurons, in the adaptive stress response and the pathological changes resulting from chronic stress. However, it is not known whether early life chronic stress affects the developing DRN activity, or whether the stress-induced changes affect 5-HT DRN neurons in a subregion- or phenotype-specific manner. To answer these questions, we use in vivo 2-photon calcium imaging of 5-HT DRN neurons in larval zebrafish exposed to chronic unpredictable stress during early life. Here, we show that early life chronic stress prevents the habituation of the serotonergic system to repeated stress-exposure by altering the balance of excitatory/inhibitory responses within the DRN. These changes are most pronounced in a subset of serotonergic cells co-expressing GABAergic markers. Using chemogenetic ablation of 5-HT DRN neurons, we show that stress-induced plasticity of the DRN contributes to changes in startle response habituation and in locomotive activity, but not in anxiety-like behaviors. Collectively, our results emphasize the role of stress-induced plasticity of DRN neurons in the selective regulation of maladaptive behavioral outcomes.

The fundamental processes of protein synthesis and autophagy are encoded by genes that vary in their essentiality for cellular fitness, and these genes are often inversely coupled through mTORC1 signaling. This study leverages analyses of gene essentiality genomic studies, to identify genes that are not only non-essential for cellular fitness, but also redundant for either protein synthesis or autophagy. This genomic approach identifies Aimp1, a highly conserved member of multi-aminoacyl tRNA synthetase complex thought to promote protein synthesis, Aimp1, as a limiter of autophagy in part through uncoupling of mTORC1 activity while minimally affecting protein synthesis. Transcriptomics analyses demonstrate that during immune responses protein synthesis and autophagy are inversely related. Depletion of Aimp1 in murine myeloid cells impairs innate immunity kinetics, thus unmasking an exemption in the inverse relationships between protein synthesis and autophagy. Our findings reveal that the functional redundancy of select protein synthesis genes, such as Aimp1, can reinforce autophagic activity, thereby challenging the canonical inverse relationship between translation and autophagy and highlighting a novel mechanism for maintaining cellular homeostasis.

Micro- and nanoplastics (MNPs) are emerging pollutants that can carry harmful substances like benzo(a)pyrene, posing potential health risks. While the harmful effects of nanoplastics on the lungs are known, how they interact with benzo(a)pyrene to affect cellular communication remains unclear. In our study, We explore this interplay using a 16-week mouse model exposed to environmentally relevant doses of polystyrene nanoplastics, benzo(a)pyrene, or a combination of both. We find that only the combined exposure leads to significant lung damage, characterized by severe inflammation and tissue scarring, which are not seen with single exposures. This combined exposure also increases oxidative stress and reduces antioxidant defenses in the lungs. Furthermore, we notice increased levels of inflammation-related molecules and markers of lung tissue damage, confirming a more severe toxic effect. Transcriptomic analysis highlights the involvement of the Relaxin signaling pathway, which influences inflammatory and tissue damage processes through PI3K-AKT and MAPK cascades; Relaxin4 activated PLC-IP3R, opening ER calcium channels and raising cytosolic Ca²⁺, which triggered macrophage extracellular trap (MET) formation. Additionally, a macrophage-MLE-12 co-culture system confirmed that Mix-induced METs are linked to the exacerbation of alveolar inflammation and the progression of pulmonary fibrosis. Our findings reveal novel molecular connections that explain how these pollutants worsen lung health, suggesting that targeting the identified signaling pathways could offer a potential approach to mitigating these harmful effects.

Granulomas are organized inflammatory lesions formed in response to persistent stimuli such as infections. Murine infection with Leishmania donovani results in granulomas in the liver, seeded by infected Kupffer cells, and serves as a well-defined model of infection-induced granuloma formation. The resolution of granulomatous inflammation requires dynamic shifts in immune-cell activation states, imposing metabolic demands. As mediators of cell signaling, lipid metabolism plays a key role in regulating inflammation and infection. How lipid changes are spatially linked to altered immune cell transcription remains unresolved. We performed a multimodal imaging analysis combining MALDI mass spectrometry, spatial and single cell transcriptomics, proteomics of flow-sorted macrophages and histopathology of L. donovani induced hepatic granulomas. Using this spatially-integrated approach, we identified LPCAT2-mediated membrane re-modelling of myeloid cells as a novel feature of these granulomas. Our study provides new insights into local immunometabolic changes associated with granuloma formation and macrophage activation.

The aberrant formation and function of neuronal synapses are recognized as major phenotypes in many cases of neurodevelopmental (NDDs) and -psychiatric disorders (NPDs). A growing body of research has identified an expanding number of susceptibility genes encoding proteins with synaptic function. Here, we present the first brain-focused characterization of a potential new susceptibility gene, ARHAGP8, which encodes a Rho GTPase activating protein (RhoGAP). Accumulating evidence suggests that ARHGAP8 plays a pivotal role in the pathogenesis of NPDs/NDDs. We provide the first evidence for ARHGAP8 as a novel player at excitatory synapses, with its synaptic localisation linked to the presence of the developmentally important NMDA receptor subunit GluN2B. By increasing ARHGAP8 levels in hippocampal neurons to mimic elevated levels found in subsets of patients, we observed reductions in dendritic complexity and spine volume, accompanied by a significant decrease in synaptic AMPA receptor-mediated transmission. These results suggest that ARHGAP8 plays a role in shaping the morphology and function of excitatory synapses, and prompt further investigation of ARHGAP8 as a candidate gene in NDDs/NPDs.