Biochemical Society transactions最新文献

Eukaryotic translation initiation factor (eIF) 3 is a multi-subunit protein complex that plays critical roles throughout translation initiation and has been implicated in a variety of human diseases. More recently, eIF3 has been tied to translation elongation and termination, as well as translational regulation. And yet, a mechanistic understanding of how eIF3 and its constituent subunits perform their canonical roles during initiation continues to elude us. Work across the last two decades has delineated broad mechanistic roles for some of these subunits and identified distinct modules of the complex that contribute differentially to the recruitment of messenger RNA (mRNA) to the ribosome during initiation. Structural approaches have further illuminated these putative roles. And yet, key mechanistic questions tied to fundamental technical challenges remain. Even so, new developments are poised to address these challenges and push our understanding of eIF3 function forward in the coming years.

Tuft cells are a rare type of epithelial cells characterized not only by their tuft-like structure but also by the expression of specific genes, including those encoding the transcription factor Pou2f3 and canonical gustatory signaling proteins. However, tuft cells can be heterogeneous in various features, both across different tissues and within the same tissue. Homeostatic tuft cells are generated from stem/progenitor cells; however, their formation and gene expression profiles are regulated epigenetically and in response to changes in their microenvironments. Ectopic formation of tuft cells, their transdifferentiation into other cell types, and dedifferentiation to stem/progenitor cells have also been found in some tissues upon severe injuries. Tuft cells function as chemosensory sentinels and can detect a variety of pathogens such as bacteria, protists, and helminths with their cell surface receptors. Activation of these receptors in turn activates intracellular signaling cascades, leading to the release of output effectors: the cytokine IL-25, the eicosanoids, and the transmitters acetyl choline and ATP, some of which act on group 2 innate lymphoid cells, triggering innate immune responses, or on neighboring epithelial cells to accelerate cilia beating and increase mucus secretion, or on the nerve terminals to initiate neuroimmune responses. Some tuft cells are also critical to inflammation resolution and tissue repair-an important part of the healing and recovery process. Further elucidation of tuft cells' ligands, respective receptors and downstream signaling pathways, and output effectors can provide more insights into these cells' pivotal roles in health and disease.

Eukaryotic DNA has been covalently modified by DNA methylation and folded into a three-dimensional conformation in the nucleus. While the functions of DNA methylation and chromosome organization have been widely discussed, respectively, the interplay between DNA methylation and chromosome organization remains less clear and needs to be further explained. In this review, we first discuss the cross-talk between DNA methylation and chromosome conformation, highlighting the complexity and importance of DNA methylation on chromosome organization. We also summarize the current methodologies that capture DNA methylation and chromosome organization individually or simultaneously in bulk and single cells. These mechanistic and methodological advancements facilitate broad interest in unveiling the interplay between DNA methylation and chromosome organization.

Protein degradation by the ubiquitin-proteasome system and autophagy are essential mechanisms that are involved in virtually all cellular activities, and their inadequate function was shown to underlie the pathogenesis of various medical conditions. Much of the study into these proteolytic systems has been focused on the components that facilitate the selective substrate identification and targeting for degradation. Given that most of the specific breakdown of proteins is mediated via their modification by ubiquitin, much research was dedicated to the enzymes which are responsible for substrate recognition and ubiquitination-E3 ubiquitin ligases. In addition to the complexity of substrate recognition and targeting for degradation, the mechanisms governing proteasome function were found to be tightly regulated, including the assembly of the different proteasomal sub-complexes, its different compositions and specialized subtypes such as the immunoproteasome, posttranslational modification of proteasomal subunits, and adaptations in its activity in face of different cellular states and stress conditions. Studies from recent years have highlighted an as-yet unexplored tier of proteasome regulation, namely its subcellular compartmentation and trafficking. Intracellular proteasome shuttling was shown to serve as an essential stress-coping mechanism in tumor cells and is emerging as a potential target for therapeutic interventions.

The molecular function of chromatin modifiers is canonically assumed to be directly related to their enzymatic activities and these activities are typically measured when investigating the molecular consequences of manipulation in model systems. However, it is increasingly apparent that chromatin modifiers exhibit various functions beyond purely their enzymatic roles and, surprisingly, this is true across many classes of so-called 'writers' and 'erasers', including histone acetylases and methylases, and histone deacetylases and demethylases. Some of the most striking examples of the catalytic-independent roles of chromatin modifiers can be demonstrated in mouse models, where catalytic-inactive-encoding mutant alleles, in contrast with null alleles, can prolong survival during embryogenesis or, even more profoundly, allow otherwise embryonic lethal mutants to be born and live into adulthood. A deep understanding of the enzymatic and non-enzymatic roles of chromatin regulators is of clear relevance to understanding how they contribute to normal biology and becomes even more relevant given that many of these factors are also now therapeutic targets in the context of disease. Since therapeutic options have expanded beyond small molecule enzymatic inhibitors to include degraders and interaction blocking modalities, the time is ripe to consider these questions. In this review, we explore the catalytic-independent functions of members of four classes of chromatin modifiers, through the lens of mouse embryogenesis where much of the limited in vivo data have been reported to date. In addition, we examine how existing mouse models can be assessed to tease apart enzymatic versus non-enzymatic requirements of chromatin modifiers.

Astrocytes are key regulators of neurogenesis, synaptogenesis, synaptic transmission and the clearance of pathological factors within the brain, while maintaining homeostasis throughout life. They also aid in the establishment and maintenance of a neurogenic niche enriched with precisely balanced growth factors, morphogens and extracellular matrix proteoglycans (PGs) to support neuronal development and function. Membrane-bound heparan sulphate (HS) PGs consist of core proteins decorated with HS glycosaminoglycan side chains, whose highly variable sulphation patterns regulate cellular signalling pathways such as Wnt and fibroblast growth factor. However, the specific contributions of astrocyte-derived and/or neuronal HSPGs within this microenvironment remain unclear. This mini-review examined our current understanding of the regulatory role of astrocyte-expressed HSPGs and their associated HS side chain structural variability. In particular, their influence on prenatal brain development, ageing and the changes occurring that contribute to neurodegeneration. We focused on the emerging concept that HS aggregation and impaired neurogenesis may serve as important preclinical contributors to Alzheimer's disease pathology. Alterations in astrocyteexpressed HS and their HSPG landscape are discussed as potential precursors to pathological HS aggregation and reactivity, shifting the focus of disease initiation to the potential compromise of the supportive astrocytic environment. We suggest that neuronal dysfunction cannot be solely attributed to neurodegeneration but must also be considered in the context of a deteriorating support system, where cells that once nurtured neurogenesis and synaptic integrity become dysfunctional contributors to disease pathology.

Multinucleated osteoclasts, generated by fusion of mononucleated precursors, play an essential role in the lifelong remodeling of our bones. Since within the physiological range of osteoclast sizes, their bone-resorbing activity grows with successive fusion events, both initiation of this fusion reaction and its switch off are tightly controlled. In this review, we discuss the mechanisms and proteins that facilitate and regulate this fusion process. The pathway of membrane rearrangements in osteoclast fusion shares many mechanistic motifs with other physiologically important cell-cell fusion processes, such as the formation of multinucleated skeletal muscle cells. However, the protein machinery involved in catalyzing these rearrangements in osteoclasts is still poorly understood. A better understanding of the mechanism of osteoclast fusion will hopefully lead to more effective approaches for treating skeletal diseases caused by excessive or insufficient bone resorption.

Mechanical forces play a pivotal role in cellular processes, acting as molecular switches that encode, store, and retrieve information, thereby facilitating a form of molecular memory. This review explores how protein unfolding and refolding under tensile loads generate history-dependent responses that regulate domain stability and function. We focus on proline isomerization as a reversible switch, enabling distinct quasi-stable states that underpin medium- to long-term mechanical memory. Leveraging insights from molecular dynamics simulations and experimental data, we propose that proline isomerization creates a graded, adaptive memory response, distinct from binary on-off switches, with implications for biomaterial design and biorobotics. This mechanism offers a framework for developing force-responsive materials with memory properties, enhancing applications in tissue engineering and soft robotics.

Protein-protein interactions (PPIs) are critical to all cellular activities. Despite having a large number of proteins, cells have spatial and temporal control over PPIs to avoid dysregulation in cellular pathways. Considerable research efforts have aimed to find new PPIs, curate PPIs from the literature and build searchable PPI databases. These databases have been widely used by experimental and computational scientists. Here we find that the PPIs captured by these databases are highly heterogeneous and concentrated on a small number of species. These issues hamper researchers from capturing the full landscape of reliable PPIs, affecting the accuracy of machine-learning models and the effectiveness of experimental designs. However, there are opportunities to fill gaps computationally and experimentally. We suggest developing a phylogenetically informed approach to test PPIs experimentally and computationally.

Stimulated transmembrane (TM) signaling mediated by plasma membrane localized receptors is central to numerous cellular processes, and their dysregulation leads to pathological conditions. Antigen (Ag) stimulated clustering of high-affinity immunoglobulin E (IgE) receptor FcεRI and its functional coupling of selective signaling components such as kinases, but not phosphatases, in the early stage of mast cell signaling represents the general paradigm of TM signaling mediated by membrane receptors lacking kinase module. It has been long thought that plasma membrane organizational features, especially ordered regions and cortical cytoskeletons network, play crucial roles in efficient spatial sorting of the signaling components. In this review, we highlight the observations made by advanced imaging and spectroscopy techniques at high spatial and temporal resolution that essentially establish novel principles of plasma membrane 'adaptivity' in regulating the initial steps of stimulated mast cell signaling involving Ag cross-linked IgE-FcεRI receptor.