Open Biology最新文献

Transmembrane proteins (TMEMs) constitute a large family of proteins that span biological membranes and are distributed across various cellular organelles, playing key roles in maintaining cellular homeostasis. Increasing evidence has revealed that dysregulation of TMEMs is closely associated with cancer development and progression. Therefore, a deeper understanding of the relationship between TMEMs and cancer is essential. Different TMEMs can function either as oncogenes or tumour suppressors, depending on the context. In this review, we explore the involvement of TMEMs in cancer, categorizing them into three groups based on their roles: oncogenic, tumour-suppressive or dual-function (both oncogenic and tumour-suppressive). We summarize the roles of various TMEMs in different cancer types, highlighting both well-characterized proteins and those identified through database screening, even if their exact molecular mechanisms remain unclear. Where possible, we include known signalling pathways associated with these TMEMs. This review highlights the critical roles of the TMEM protein family and encourages further research into their mechanisms, prognostic value and potential as targets for cancer therapy.

Exploring the evolution of gene networks associated with metabolic/energetic homeostasis can yield key insights into the adaptive landscapes governing the physiology of extant lineages. Here, we investigate a key hormonal module of energy metabolism in reptiles. Ghrelin (GHRL), also known as the 'hunger hormone', is a multifunctional gastric peptide, involved in appetite, food intake and body weight regulation. We examined the genomes of 112 species comprising members of the Squamata, Testudines, Crocodilia and Rhynchocephalia and provided ample evidence that GHRL was independently lost in snakes (32 species), chameleons (four species) and toadhead agamas (two species). In accordance, the enzyme responsible for ghrelin acylation and essential for its activity, MBOAT4 (membrane bound O-acyltransferase domain containing 4), is also eroded in these lineages. We suggest that the loss of this hormonal signalling system parallels critical modifications in energy metabolism, such as lower energy expenditure during rest, possibly linked with their unique ability to undergo large periods of fasting.

Ageing and age-related diseases are the result of complex biological processes that progressively cause deterioration of cellular and tissue function. Among the key hallmarks of ageing are epigenetic alterations and genomic instability, both of which are closely interconnected and significantly contribute to the ageing process. The epigenome, encompassing both DNA and histone modifications, regulates gene expression and maintains genomic integrity throughout life. With age, these regulatory systems become dysregulated, leading to genome-wide changes in chromatin structure, histone modifications and the reactivation of transposable elements (TEs). TEs, typically silenced in heterochromatic regions, become active in aged cells, contributing to genomic instability, mutagenesis, inflammation and metabolic disruption. Despite their significant implications, the role of TEs in the ageing process remains underexplored, and the interplay between epigenomic remodelling and TE activity remains poorly understood. In this review, we explore the molecular mechanisms underlying epigenetic alterations and TE reactivation during ageing, the impact of these changes on genomic stability and the potential therapeutic interventions targeting this interplay. By deciphering the role of epigenetic modifications and TE derepression in the ageing process, we aim to highlight novel avenues for anti-ageing and pro-longevity strategies.

Fucosyltransferase 8 (FUT8), a glycosyltransferase responsible for core fucosylation, is overexpressed in numerous cancers and promotes many malignant processes such as cell proliferation, invasion and migration. Transforming growth factor-β (TGF-β) stimulation promotes epithelial-mesenchymal transition (EMT), a pivotal process indicating the invasion and metastasis of glioblastoma (GBM). However, the mechanism underlying the impact of FUT8 on the TGF-β signalling pathway in GBM progression remains largely unexplored. Our data revealed that FUT8 was highly expressed in patients with GBM and was associated with poor outcomes. FUT8 knockdown inhibited TGF-β-induced EMT, whereas FUT8 overexpression promoted TGF-β-induced EMT in vitro and in vivo. Mechanistic investigations revealed that FUT8 expression increased during TGF-β stimulation. In addition, the core fucosylation of TGF-β receptor complexes decreased after FUT8 knockdown. Moreover, the expression of E2F4, a transcription factor upregulated upon TGF-β stimulation, was shown to directly regulate the expression of FUT8 via a TGF-β-induced non-Smad signalling pathway. Our results elucidated a new mechanism facilitated by E2F4-FUT8-mediated receptor core fucosylation that promotes TGF-β signalling and EMT, ultimately driving the invasion and metastasis of GBM cells.

Necroptosis is a form of regulated cell death (RCD) that evolved as a defence against pathogenic infection. Unlike caspase-dependent RCD, necroptosis, in its canonical form, is driven by receptor-interacting protein kinase 1 and 3 (RIPK1 and RIPK3) signalling, culminating in the activation of the pseudokinase mixed lineage kinase domain-like protein (MLKL). Central to this process is the interaction between MLKL and its upstream regulator, RIPK3, forming a functional module called the necrosome that governs the spatiotemporal execution of cell death. Despite progress in our understanding of necroptotic signalling, key open questions remain. The structural organization of MLKL influences its interaction with RIPK3, yet the precise features of their binding surfaces and their regulation are not fully resolved. Additionally, the high-order supramolecular assembly of the necrosome and its transition between different states remain poorly understood, particularly regarding how RIPK3 and MLKL configurations impact necrosome activity and stability. In this review, we summarize current knowledge on the evolution, structure and regulation of the RIPK3-MLKL axis and discuss models of their activation in light of recent discoveries.

The endoplasmic reticulum (ER) is an interconnected network of membrane-bound tubules and sheets stretching throughout the cytoplasm of all eukaryotic cells including plant cells. The ER is highly dynamic and undergoes constant remodelling. A properly formed ER is essential for cell growth, development and cellular responses to stresses. It is known that the dynamics of the cytoskeleton is linked to the formation and/or remodelling of a functional ER. Over the past 20 years, research has revealed that a set of ER localized ER-shaping proteins play crucial roles in building a functional ER. Recent research also indicates that maintaining a functional ER, in particular under stressful conditions, requires a proper turnover of the ER mediated by selective autophagy of the ER. In this review, we discuss the current understanding of functions of reticulons and atlastins, two classes of ER-shaping proteins in the formation of the ER in both animal and plant cells, with an emphasis on the plant system. We also discuss how the two classes of proteins may interplay to maintain a proper ER and how their actions may be regulated. Finally, we briefly mention how autophagy of the ER may be regulated during cell development and stress responses.

The actions of animals provide a window into how their minds work. Recent advances in deep learning are providing powerful approaches to recognize patterns of animal movement from video recordings using markerless pose estimation models. Current methods for classifying animal behaviour using the outputs of these models often rely on species and task-specific feature engineering of trajectories, kinematics and task programming. Generalized solutions that use only pose estimations and the inherent structure of animals and their environment provide an opportunity to develop foundational, contextual and, importantly, standardized animal behaviour models for efficient and reproducible behavioural analysis. Here, we present PoseRecognition (PoseR), a behavioural classifier using spatio-temporal graph convolutional networks. We show that it can be used to classify animal behaviour quickly and accurately from pose estimations, using zebrafish larvae, Drosophila melanogaster, mice and rats as model organisms. Our easily accessible tool simplifies the behavioural analysis workflow by transforming coordinates of animal position and pose into semantic labels with speed and precision. The design of our tool ensures scalability and versatility for use across multiple species and contexts, improving the efficiency of behavioural analysis across fields.

Endometrial receptivity occurs during a limited time in the menstrual cycle called the 'window of implantation' (WOI) and is required for successful implantation. Endometrial luminal epithelial cells become adhesive to facilitate embryo attachment and implantation; however, how this occurs is poorly understood. We recently identified that myosin heavy chain 10 (MYH10) was abnormally downregulated in infertile organoid endometrial epithelial cells during the WOI, suggesting a role in receptivity. MYH10 regulates cell polarity, adhesion and migration; however, whether it regulates receptivity is unknown. Our research investigated whether MYH10 regulates endometrial epithelial cell adhesive capacity. MYH10 is localized to all major cellular compartments within the endometrium. Immunostaining intensity was higher in luminal epithelial cells during the WOI compared to the proliferative phase in fertile endometrium. However, MYH10 staining was decreased in infertile endometrium. siRNA knockdown of MYH10 in the Ishikawa cell line significantly decreased cell adhesion to human cytotrophoblast-progenitor spheroids. MYH10 knockdown increased PGR and FOXO1 while decreasing PDLIM2 expression. Proteomics analysis following MYH10 knockdown demonstrated altered production of 57 proteins with functions critical in receptivity, including tight junctions. These results demonstrate that MYH10 alters endometrial epithelial cell adhesive capacity primarily via regulation of the actin cytoskeleton, implying an important role in implantation.

Clonal populations exhibit phenotypic variation despite being composed of genetically identical cells under the same environmental conditions. The proliferation rate also shows this heterogeneity, but the underlying mechanisms remain poorly understood. In this study, we combined single-cell microencapsulation with confocal microscopy to develop a new experimental approach for analysing budding yeast cell lineages and determining the age of every cell within each microcolony. We found that most slow-growing lineages are founded by young mother cells that have undergone only a few cell divisions, typically between one and four. This reduction in proliferative capacity is linked to the expression levels of the cell cycle regulator Whi5, which increase with the number of replication cycles, even since the earliest stages. We also found that the increased levels of Whi5 are due to the higher accumulation of its mRNA during the S/G2/M phases of young mother cells compared to newborn cells. Our results show that the proliferative structure of a cell population is progressively shaped in each mitotic cycle, starting from the very first division, when a mother cell has the opportunity to establish a slowly proliferating lineage. Possible mechanisms of Whi5 action to mediate this effect are discussed.

Multicellularity emerges from the ability of cells to undergo functional differentiation. One of the key mechanisms that enables this coordination is cellular signalling-a series of molecular interactions within or between cells that induce changes in cell behaviour or gene expression. As the body plan of multicellular organisms becomes more complex, so does the sophistication of their signalling systems. The Wnt and Notch pathways are central to regulating cell fate, tissue development and maintenance in all studied metazoa. Affecting overlapping biological processes, often within short developmental time windows, these molecular systems appear to be functionally interconnected, leading to the proposal of a 'Wntch' signalling concept. This concept implies that Wnt and Notch modules do not operate as isolated linear pathways but form a coherent network that integrates signals to ensure precise control of developmental and physiological outcomes. In this review, we synthesize both past and recent insights into the direct crosstalk of Wnt and Notch signalling molecules, examine crosstalk within the context of recently developed assays such as single-cell RNA sequencing and proximity labelling, and discuss the broader implications of this interplay in development and disease.