Biochemical Society transactions最新文献

In the gastrointestinal (GI) tract, food is digested and absorbed while GI hormones are secreted from the enteroendocrine cells (EECs). These hormones regulate food intake, glucose homeostasis, digestion, GI motility, and metabolism. Although ECCs may express more than a single hormone, the ECCs usually secrete only one or a few hormones. The pattern of EEC secretion varies along the length of the GI tract as the different EEC types are scattered in different densities along the GI tract. Following bariatric surgery, a postprandial hypersecretion of certain GI hormones occurs which contributes to the postsurgery weight loss. Mimicking this postprandial hypersecretion of GI hormones by targeting endogenous EEC secretion, using specific modulators of receptors, ion channels, and transporters found on specific EECs, to induce weight loss is a current research aim. To achieve this, a more complete understanding of the release mechanisms, expression of receptors, transporters, and the secretion pattern of the different ECC types is needed. Using the vascularly perfused intestinal model, it is possible to obtain a detailed knowledge of these release mechanisms by evaluating the effects on secretion of blocking or stimulating specific receptors, ion channels, and transporters as well as evaluating nutrient handling and absorption in each of the different sections of the intestine. This mini-review will focus on how the isolated perfused intestine has been used in our group as a model to investigate the nutrient-induced release mechanisms of ECCs with a focus on glucagon-like peptide-1 secreting cells.

Cilia and eukaryotic flagella (exchangeable terms) function in cell motility and signaling, which are pivotal for development and physiology. Cilia dysfunction can lead to ciliopathies. Cilia are usually assembled in quiescent and/or differentiated cells and undergo disassembly when cells enter cell cycle or in response to environmental stresses. Cilia contain a microtubule-based structure termed axoneme that comprises nine outer doublet microtubules with or without a pair of central microtubules, which is ensheathed by the ciliary membrane. Regulation of the axonemal microtubule dynamics is tightly associated with ciliary assembly and disassembly. In this short review, we discuss recent findings on the regulation of axonemal microtubules by microtubule-binding proteins and microtubule modulating kinesins during ciliary assembly and disassembly.

Biological carbohydrate polymers represent some of the most complex molecules in life, enabling their participation in a huge range of physiological functions. The complexity of biological carbohydrates arises from an extensive enzymatic repertoire involved in their construction, deconstruction and modification. Over the past decades, structural studies of carbohydrate processing enzymes have driven major insights into their mechanisms, supporting associated applications across medicine and biotechnology. Despite these successes, our understanding of how multienzyme networks function to create complex polysaccharides is still limited. Emerging techniques such as super-resolution microscopy and cryo-electron tomography are now enabling the investigation of native biological systems at near molecular resolutions. Here, we review insights from classical in vitro studies of carbohydrate processing, alongside recent in situ studies of glycosylation-related processes. While considerable technical challenges remain, the integration of molecular mechanisms with true biological context promises to transform our understanding of carbohydrate regulation, shining light upon the processes driving functional complexity in these essential biomolecules.

Nucleosomes, the building block of chromatin, are responsible for regulating access to the DNA sequence. This control is critical for essential cellular processes, including transcription and DNA replication and repair. Studying chromatin can be challenging both in vitro and in vivo, leading many to use a mono-nucleosome system to answer fundamental questions relating to chromatin regulators and binding partners. However, the mono-nucleosome fails to capture essential features of the chromatin structure, such as higher-order chromatin folding, local nucleosome-nucleosome interactions, and linker DNA trajectory and flexibility. We briefly review significant discoveries enabled by the mono-nucleosome and emphasize the need to go beyond this model system in vitro. Di-, tri-, and tetra-nucleosome arrays can answer important questions about chromatin folding, function, and dynamics. These multi-nucleosome arrays have highlighted the effects of varying linker DNA lengths, binding partners, and histone post-translational modifications in a more chromatin-like environment. We identify various chromatin regulatory mechanisms yet to be explored with multi-nucleosome arrays. Combined with in-solution biophysical techniques, studies of minimal multi-nucleosome chromatin models are feasible.

Large conductance voltage- and calcium-activated potassium channels (BK channels) are extensively found throughout the central nervous system and play a crucial role in various neuronal functions. These channels are activated by a combination of cell membrane depolarisation and an increase in intracellular calcium concentration, provided by calcium sources located close to BK. In 2001, Isaacson and Murphy first demonstrated the coupling of BK channels with N-methyl-D-aspartate receptors (NMDAR) in olfactory bulb neurons. Since then, additional evidence has confirmed this functional coupling in other brain regions and highlighted its significance in neuronal function and pathophysiology. In this review, we explore the current understanding of these macrocomplexes in the brain, the molecular mechanisms behind their interactions and their potential roles in neurodevelopmental disorders, paving the way for new treatment strategies.

Coxiella burnetii, the causative agent of human Q fever, is an obligate intracellular bacterial pathogen that replicates in a large, membrane-bound vacuole known as the Coxiella Containing Vacuole (CCV). The CCV is a unique, phagolysosome-derived vacuole with a sterol-rich membrane containing host and bacterial proteins. The CCV membrane itself serves as a barrier to protect the bacteria from the host's innate immune response, and the lipid and protein content directly influence both the CCV luminal environment and interactions between the CCV and host trafficking pathways. CCV membrane cholesterol is critical in regulating CCV pH, while CCV phosphatidylinositol phosphate species influence CCV fusion events and membrane dynamics. C. burnetii proteins directly target host lipid metabolism to regulate CCV membrane content and generate a source of lipids that support bacterial replication or influence the innate immune response. This review provides an overview of the diverse repertoire of lipids involved in CCV formation and maintenance, highlighting the pathogen-driven strategies to modify host lipid homeostasis.

NLRP3 is an inflammasome seeding pattern recognition receptor that initiates a pro-inflammatory signalling cascade in response to changes in intracellular homeostasis that are indicative of bacterial infection or tissue damage. Several types of post-translational modification (PTM) have been identified that are added to NLRP3 to regulate its activity. Recent progress has revealed that NLRP3 is subject to a further type of PTM, S-acylation (or palmitoylation), which involves the reversible addition of long-chain fatty acids to target cysteine residues by opposing sets of enzymes. This review provides an overview of recent studies that have identified S-acylation as an important modifier of NLRP3 function. The essential role of S-acylation in the recruitment of NLRP3 to intracellular membranes and the consequences of S-acylation-dependent membrane recruitment on NLRP3 localisation and activation are discussed in detail.

Biological mechanotransduction enables cells to sense and respond to mechanical forces in their local environment through changes in cell structure and gene expression, resulting in downstream changes in cell function. However, the complexity of living systems obfuscates the mechanisms of mechanotransduction, and hence the study of these processes in vitro has been critical in characterising the function of existing mechanosensitive membrane proteins. Synthetic cells are biomolecular compartments that aim to mimic the organisation, functionality and behaviours of biological systems, and represent the next step in the development of in vitro cell models. In recent years, mechanosensitive channels have been incorporated into synthetic cells to create de novo mechanosensitive signalling pathways. Here, I will discuss these developments, from the molecular parts used to construct existing pathways, the functionality of such systems, and potential future directions in engineering synthetic mechanotransduction. The recapitulation of mechanotransduction in synthetic biology will facilitate an improved understanding of biological signalling through the study of molecular interactions across length scales, whilst simultaneously generating new biotechnologies that can be applied as diagnostics, microreactors and therapeutics.

Primary axis formation is the first step of embryonic patterning in flowering plants and recent findings highlight the importance of parent-of-origin effects in this process. Apical-basal patterning has a strong influence on suspensor development, an extra-embryonic organ involved in nutrient transport to the embryo at an early stage of seed development. The endosperm, a second fertilization product, nourishes the embryo at later stages of seed development. Parent-of-origin effects are phenotypic effects that depend on whether a causal gene is inherited from the mother or the father. They are discussed in the context of the parental conflict theory in relation to nutrient allocation to the offspring. Imprinting is an important mechanism leading to uniparental gene expression in the endosperm and maternal control of its development. The parental conflict theory would predict that, with limited resources available, there is a competition between paternal alleles to increase nutrient supply, allowing rapid development and seed filling. A parental conflict might therefore shape the evolution of genes that can influence the allocation of nutrients to the seeds. However, we will also discuss other possible causes that might select genes for uniparental contribution. New data show that parent-of-origin effects also occur during the early stages of embryo development. These appear to be caused primarily by the carry-over of gamete-derived factors. In this review, we will highlight the molecular pathways that control apical-basal patterning in the early embryo and discuss recent findings in the context of the parental conflict theory and alternative explanations.

Many prokaryotic and eukaryotic cells store inorganic phosphate in the form of polymers called polyphosphate (polyP). There has been an explosion of interest in polyP over the past decade, in part due to newly suggested roles related to diverse aspects of human health. The physical interaction of polyP chains with specific proteins has been proposed to regulate cellular homeostasis and modulate signaling pathways in response to environmental changes. Recently, several studies have challenged existing models for how polyP interacts with its protein targets, while identifying new motifs that are capable of binding to polyP. In this review, we summarize these findings, delineate the functional implications for polyP-protein interactions at the molecular level, and define open questions that should be addressed to propel the field forward.