Open Biology最新文献

The physiological state of an insect can affect its olfactory system. However, the molecular mechanism underlying the effect of nutrition-dependent states on odour-guided behaviours in hoverflies remains unclear. In this study, comparative transcriptome analysis of the antenna and proboscis from Eupeodes corollae under different feeding states was conducted. Compared with the previously published antennal transcriptome, a total of 32 novel chemosensory genes were identified, including 4 ionotropic receptors, 17 gustatory receptors, 9 odorant binding proteins and 2 chemosensory proteins. Analysis of differences in gene expression between different feeding states in male and female antennae and proboscises revealed that the expression levels of chemosensory genes were impacted by feeding state. For instance, the expression levels of EcorOBP19 in female antennae, EcorOBP6 in female proboscis, and EcorOR6, EcorOR14, EcorIR5 and EcorIR84a in male antennae were significantly upregulated after feeding. On the other hand, the expression levels of EcorCSP7 in male proboscis and EcorOR40 in male antennae were significantly downregulated. These findings suggest that nutritional state plays a role in the adaptation of hoverflies' olfactory system to food availability. Overall, our study provides important insights into the plasticity and adaptation of chemosensory systems in hoverflies.

The 14-3-3 proteins are a highly conserved adaptor protein family with multi-layer functions, abundantly expressed in the brain. The 14-3-3 proteins modulate phosphorylation, regulate enzymatic activity and can act as chaperones. Most importantly, they play an important role in various neurodegenerative disorders due to their vast interaction partners. Particularly, the 14-3-3ζ isoform is known to co-localize in aggregation tangles in both Alzheimer's and Parkinson's diseases as a result of protein-protein interactions. These abnormal clumps consist of amyloid fibrils, insoluble aggregates, mainly formed by the amyloid-β, tau and α-synuclein proteins. However, the molecular basis of if and how 14-3-3ζ can aggregate into amyloid fibrils is unknown. In this study, we describe the formation of amyloid fibrils by 14-3-3ζ using a comprehensive approach that combines bioinformatic tools, amyloid-specific dye binding, secondary structure analysis and atomic force microscopy. The results presented herein characterize the amyloidogenic properties of 14-3-3ζ and imply that the well-folded protein undergoes aggregation to β-sheet-rich amyloid fibrils.

The protein homeostasis network keeps proteins in their correct shapes and avoids unwanted aggregation. In turn, the accumulation of aberrantly misfolded proteins has been directly associated with the onset of ageing-associated neurodegenerative diseases such as Alzheimer's and Parkinson's. However, a detailed and rational understanding of how protein homeostasis is achieved in health, and how it can be targeted for therapeutic intervention in diseases remains missing. Here, large-scale single-cell expression data from the Allen Brain Map are analysed to investigate the transcription regulation of the core protein homeostasis network across the human brain. Remarkably, distinct expression profiles suggest specialized protein homeostasis networks with systematic adaptations in excitatory neurons, inhibitory neurons and non-neuronal cells. Moreover, several chaperones and Ubiquitin ligases are found transcriptionally coregulated with genes important for synapse formation and maintenance, thus linking protein homeostasis to the regulation of neuronal function. Finally, evolutionary analyses highlight the conservation of an elevated interaction density in the chaperone network, suggesting that one of the most exciting aspects of chaperone action may yet be discovered in their collective action at the systems level. More generally, our work highlights the power of computational analyses for breaking down complexity and gaining complementary insights into fundamental biological problems.

Mitochondria, classically known as the powerhouse of cells, are unique double membrane-bound multifaceted organelles carrying a genome. Mitochondrial content varies between cell types and precisely doubles within cells during each proliferating cycle. Mitochondrial content also increases to a variable degree during cell differentiation triggered after exit from the proliferating cycle. The mitochondrial content is primarily maintained by the regulation of mitochondrial biogenesis, while damaged mitochondria are eliminated from the cells by mitophagy. In any cell with a given mitochondrial content, the steady-state mitochondrial number and shape are determined by a balance between mitochondrial fission and fusion processes. The increase in mitochondrial content and alteration in mitochondrial fission and fusion are causatively linked with the process of differentiation. Here, we critically review the quantitative aspects in the detection methods of mitochondrial content and shape. Thereafter, we quantitatively link these mitochondrial properties in differentiating cells and highlight the implications of such quantitative link on stem cell functionality. Finally, we discuss an example of cell size regulation predicted from quantitative analysis of mitochondrial shape and content. To highlight the significance of quantitative analyses of these mitochondrial properties, we propose three independent rationale based hypotheses and the relevant experimental designs to test them.

RasG is a major regulator of macropinocytosis in Dictyostelium discoideum. Its activity is under the control of an IQGAP-related protein, IqgC, which acts as a RasG-specific GAP (GTPase activating protein). IqgC colocalizes with the active Ras at the macropinosome membrane during its formation and for some time after the cup closure. However, the loss of IqgC induces only a minor enhancement of fluid uptake in axenic cells that already lack another RasGAP, NF1. Here, we show that IqgC plays an important role in the regulation of macropinocytosis in the presence of NF1 by restricting the size of macropinosomes. We further provide evidence that interaction with RasG is indispensable for the recruitment of IqgC to forming macropinocytic cups. We also demonstrate that IqgC interacts with another small GTPase from the Ras superfamily, Rab5A, but is not a GAP for Rab5A. Since mammalian Rab5 plays a key role in early endosome maturation, we hypothesized that IqgC could be involved in macropinosome maturation via its interaction with Rab5A. Although an excessive amount of Rab5A reduces the RasGAP activity of IqgC in vitro and correlates with IqgC dissociation from endosomes in vivo, the physiological significance of the Rab5A-IqgC interaction remains elusive.

Plants deploy cell-surface and intracellular receptors to detect pathogen attack and trigger innate immune responses. Inside host cells, families of nucleotide-binding/leucine-rich repeat (NLR) proteins serve as pathogen sensors or downstream mediators of immune defence outputs and cell death, which prevent disease. Established genetic underpinnings of NLR-mediated immunity revealed various strategies plants adopt to combat rapidly evolving microbial pathogens. The molecular mechanisms of NLR activation and signal transmission to components controlling immunity execution were less clear. Here, we review recent protein structural and biochemical insights to plant NLR sensor and signalling functions. When put together, the data show how different NLR families, whether sensors or signal transducers, converge on nucleotide-based second messengers and cellular calcium to confer immunity. Although pathogen-activated NLRs in plants engage plant-specific machineries to promote defence, comparisons with mammalian NLR immune receptor counterparts highlight some shared working principles for NLR immunity across kingdoms.

Natural killer (NK) cell deficiency (NKD) is a rare disease in which NK cell function is reduced, leaving affected individuals susceptible to repeated viral infections and cancer. Recently, a patient with NKD was identified carrying compound heterozygous variants of MCM10 (minichromosome maintenance protein 10), an essential gene required for DNA replication, that caused a significant decrease in the amount of functional MCM10. NKD in this patient presented as loss of functionally mature late-stage NK cells. To understand how MCM10 deficiency affects NK cell development, we generated MCM10 heterozygous (MCM10^+/-) induced pluripotent stem cell (iPSC) lines. Analyses of these cell lines demonstrated that MCM10 was haploinsufficient, similar to results in other human cell lines. Reduced levels of MCM10 in mutant iPSCs was associated with impaired clonogenic survival and increased genomic instability, including micronuclei formation and telomere erosion. The severity of these phenotypes correlated with the extent of MCM10 depletion. Significantly, MCM10^+/- iPSCs displayed defects in NK cell differentiation, exhibiting reduced yields of hematopoietic stem cells (HSCs). Although MCM10^+/- HSCs were able to give rise to lymphoid progenitors, these did not generate mature NK cells. The lack of mature NK cells coincided with telomere erosion, suggesting that NKD caused by these MCM10 variants arose from the accumulation of genomic instability including degradation of chromosome ends.

Although the mechanisms by which schistosomes grow and develop in humans are poorly defined, their unique outer tegument layer, which interfaces with host blood, is considered vital to homeostasis of the parasite. Here, we investigated the importance of tegument lipid rafts to the biology of Schistosoma mansoni in the context of host-parasite interactions. We demonstrate the temporal clustering of lipid rafts in response to human epidermal growth factor (EGF) during early somule development, concomitant with the localization of anteriorly orientated EGF receptors (EGFRs) and insulin receptors, mapped using fluorescent EGF/insulin ligand. Methyl-β-cyclodextrin (MβCD)-mediated depletion of cholesterol from lipid rafts abrogated the EGFR/IR binding at the parasite surface and led to modulation of protein kinase C, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and Akt signalling pathways within the parasite. Furthermore, MβCD-mediated lipid raft disruption, and blockade of EGFRs using canertinib, profoundly reduced somule motility and survival, and attenuated stem cell proliferation and somule growth and development particularly to the fast-growing liver stage. These findings provide a novel paradigm for schistosome development and vitality in the host, driven through host-parasite interactions at the tegument, that might be exploitable for developing innovative therapeutic approaches to combat human schistosomiasis.

Ribosomal protein uS10, a product of the RPS20 gene, is an essential constituent of the small (40S) subunit of the human ribosome. Disruptive mutations in its gene are associated with a predisposition to hereditary colorectal carcinoma. Here, using HEK293T cells, we show that a deficiency of this protein leads to a decrease in the level of ribosomes (ribosomal shortage). RNA sequencing of the total and polysome-associated mRNA samples reveals hundreds of genes differentially expressed in the transcriptome (t)DEGs and translatome (p)DEGs under conditions of uS10 deficiency. We demonstrate that the (t)DEG and (p)DEG sets partially overlap, determine genes with altered translational efficiency (TE) and identify cellular processes affected by uS10 deficiency-induced ribosomal shortage. We reveal that translated mRNAs of upregulated (p)DEGs and genes with altered TE in uS10-deficient cells are generally more abundant and that their GC contents are significantly lower than those of the respective downregulated sets. We also observed that upregulated (p)DEGs have longer coding sequences. Based on our findings, we propose a combinatorial model describing the process of reorganization of mRNA translation under conditions of ribosomal shortage. Our results reveal rules according to which ribosomal shortage reorganizes the transcriptome and translatome repertoires of actively proliferating cells.