搜索结果：Biochemical Society transactions

Cancer cells face continual stressors, which they must overcome to proliferate and survive in the body. Under these conditions, essential biochemical pathways are disrupted, contributing to various stress responses that either promote adaptation and survival or eventual cell death. The evolutionarily conserved integrated stress response (ISR) is a key adaptive mechanism that transiently rewires the transcriptome and translatome in response to various stressors. While the ISR is activated in healthy cells under moderate stress, cancers especially rely on this pathway to overcome harsh conditions experienced during tumor growth and metastasis. We explore the pro-tumorigenic role of the ISR, along with the upstream stress-sensing kinases that activate it. These include protein kinase R-like endoplasmic reticulum kinase, general control non-derepressible 2, double-stranded RNA-dependent protein kinase, and heme-regulated eukaryotic translation initiation factor 2α kinase (HRI), which initiate an ISR in response to diverse stressors by phosphorylating their shared substrate, eukaryotic initiation factor-2α. An in-depth understanding of the pro-survival functions of the ISR and the contexts in which it is pro-tumorigenic is necessary to leverage the ISR as a therapeutic strategy.

As the optimal source of nutrition for infants, investigations into the human milk lipidome have been quite extensive. Much of the work, however, has been focused on major lipid components such as triglycerides, possibly undermining its actual complexity. This review focuses on two minor but bioactive lipid classes in human milk: fatty acid esters of hydroxy fatty acids (FAHFAs) and alkyl-diacylglycerols (TG(O)s). FAHFAs are known to exhibit anti-diabetic and anti-inflammatory effects, while TG(O)s are important for the prevention of childhood obesity. With the knowledge that early nutrition and metabolic health influence the risk of metabolic dysfunctions later in life, a comprehensive understanding of FAHFAs and TG(O)s, along with reliable characterisations in human milk, would better allow for the development of accurate human milk fat substitutes. This could have future implications as alternative or preventive treatments for infants with early markers of metabolic dysfunction, including diabetes and obesity. The structural characteristics, pathways for biosynthesis and degradation, bioactivity, dietary sources, and characterisations of FAHFAs and TG(O)s in human milk are discussed. Their statuses as emerging lipid classes, however, is reflected in the incomplete understanding of their biochemical pathways. Characterisations of FAHFAs and TG(O)s in human milk are relatively poor, and contradicting results are reported. This review also addresses the challenges involved in the study of minor lipids in complex biological matrices, and the possible reasons underlying the slower evolution of our understanding of FAHFAs and TG(O)s in human milk and their associations with health outcomes.

Initially identified through chromosomal translocations in lymphomas, the BCL7 protein family, comprising the three paralogues BCL7A, BCL7B, and BCL7C, has recently emerged as a core component of mammalian SWI/SNF ATP-dependent chromatin remodeling complexes. Although their functions remained poorly understood for many years, recent structural and biochemical studies have substantially improved our understanding of their roles. Cryo-electron microscopy studies revealed that BCL7 proteins interact with nucleosomes through a conserved N-terminal arginine anchor motif that binds the nucleosomal acidic patch and stabilize the actin-related protein module through a conserved β-hairpin motif. These findings identify BCL7 proteins as structural elements that contribute to nucleosome engagement and SWI/SNF complex integrity. Comparative analyses further suggest that key structural features of BCL7 proteins are conserved across evolution despite limited sequence similarity. In addition to their roles in chromatin remodeling, increasing evidence links BCL7 proteins to hematological malignancies, solid tumors, and developmental disorders, highlighting their emerging value as biomarkers and potential therapeutic targets. This review summarizes current knowledge on the structure, evolution, and functions of the BCL7 family and outlines future directions for elucidating their contribution to chromatin regulation and disease.

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is one of the most frequently inactivated tumor suppressors in human cancers, serving as a critical negative regulator of phosphatidylinositol 3-kinase (PI3K)-AKT signaling. Although genetic mutation or deletion commonly underlie functional PTEN loss, accumulating evidence indicates that post-transcriptional and post-translational mechanisms also substantially contribute to PTEN suppression. Phosphatases of regenerating liver (PRLs), comprising PRL1, PRL2, and PRL3, are oncogenic phosphatases frequently overexpressed in both solid and hematological malignancies. Emerging studies reveal that PRLs can downregulate PTEN through a post-translational mechanism by direct dephosphorylation of PTEN at Tyr336, therefore promoting PTEN ubiquitination and proteasomal degradation. PRLs can also reduce PTEN expression through a post-transcriptional mechanism by dephosphorylating the inhibitory Tyr570 in JAK2, thereby activating the JAK2/STAT3-mediated miR-21 expression. These coordinated actions collectively amplify PI3K-AKT signaling, consequently promoting proliferation, survival, and metastasis. In the present review, we synthesize current knowledge of PRL structure, evolution, and functional diversity, evaluate genetic, biochemical, and organismal evidence linking PRLs to PTEN regulation, and discuss insights on PRL oncogenicity derived from experimental models. We further examine context-dependent functions of PRLs, unresolved questions regarding catalytic versus scaffold activities, and the therapeutic potential of targeting the PRL-PTEN axis. Understanding how PRLs modulate PTEN activity may reveal new strategies to restore tumor suppressor function in PTEN-deficient cancers.

Organelle contact sites are highly dynamic and specialized regions where distinct organelles come into proximity, enabling direct inter-organelle communication. These structures play fundamental roles in cellular homeostasis by coordinating the exchange of lipids, metabolites, and ions, as well as regulating key processes such as organelle dynamics, mitochondrial fission, autophagy, and metabolic integration. Alterations in contact site architecture and function have been increasingly associated with a wide range of human diseases, including neurodegeneration, metabolic disorders, and cancer. Despite their biological relevance, the nanoscale nature and dynamic behaviour of contact sites have historically posed significant challenges for their accurate detection and functional characterization. Here, we provide a comprehensive overview of the methodologies currently available to study organelle contact sites, ranging from classical approaches such as electron microscopy and biochemical fractionation to advanced imaging techniques and genetically encoded reporters. We discuss recent developments in high-resolution and live-cell microscopy that have improved the spatial and temporal resolution of contact site analysis, as well as emerging tools designed to selectively label, quantify, and manipulate these interfaces. Attention is given to the next generation of engineered reporters capable of sensing molecular and ionic exchanges at contact sites, thereby moving beyond structural description toward functional interrogation. By critically evaluating the strengths and limitations of existing approaches, we aim to provide a framework for selecting appropriate tools and to highlight future directions in the field. Ultimately, advancing our ability to monitor and dissect organelle contact sites will be essential for understanding their contribution to cellular physiology and disease.

Breast cancer is associated with a highly fibrotic tumour microenvironment, where cancer-associated fibroblasts (CAFs) secrete excessive amounts of extracellular matrix (ECM). Fibrosis and collagen deposition correlate with poor patient survival, indicating that the ECM plays a role in promoting tumorigenesis. The ECM is constantly remodelled through extracellular and intracellular degradation pathways. While protease-dependent extracellular ECM degradation has been well studied, the intracellular degradation pathway is less understood. Here, I will describe the evidence supporting a role for ECM internalisation and lysosomal degradation in promoting breast cancer progression. Both cancer cells and CAFs are reported to uptake ECM components via different ECM receptors. These include TEM8 in fibroblasts, Endo180 in both cancer cells and CAFs, and α2β1 integrin in cancer cells. Importantly, this process has been associated with metabolic reprogramming under nutrient deprivation conditions representative of the breast cancer TME, cancer cell growth in vitro and in vivo, and cancer cell migration and invasion. Therefore, regulators of ECM endocytosis and lysosomal delivery might represent novel potential targets to prevent tumour growth and metastasis in ECM-rich breast cancers.

The transforming growth factor-beta (TGF-β) superfamily is crucial for regulating cell proliferation, differentiation, migration, and tissue homeostasis, and plays a central role in embryonic development and function of tissues and organs. Dysregulation of these pathways contributes to a broad spectrum of diseases, including cancer, fibrosis, and developmental disorders. The present review explores how the primary cilium, a specialized signaling organelle, orchestrates TGF-β superfamily signaling, with a focus on emerging evidence of its role in heart and brain development, as well as in tissue homeostasis.

ATP-binding cassette (ABC) transporters are essential membrane proteins that couple ATP hydrolysis to move diverse substrates across lipid bilayers through large-scale conformational changes. In humans, 48 ABC transporters span seven subfamilies (A-G); within these, the ABCA subfamily mediates cellular lipid handling in contexts ranging from neural function to pulmonary surfactant production, and its dysfunction contributes to human disease from cardiovascular disorders to Alzheimer's. These diverse physiological roles all depend on precise lipid translocation within or across membrane systems, a shared principle that is often underemphasized in broad "lipid-transporter" classifications. This review summarizes the structural landscape of the ABCA family and re-examines the mechanistic insights that have emerged. We compare and contrast transport models derived from detergent-solubilized and lipid-embedded structures, with particular emphasis on lipid-embedded ABCA7, which supports a membrane-integrated mechanism in which the bilayer itself contributes to the transport pathway. We highlight shared rigid-body transitions, outline open questions surrounding transport directionality and protein-lipid coupling, and suggest that future models should treat the membrane not merely as a passive scaffold but as an integral component of the transport mechanism, while recognizing that membrane-integrated behavior is currently established structurally only for ABCA7 and remains a working hypothesis for other family members.

The first heme oxygenase-like dimetal oxidase/oxygenase (HDO) was functionally validated through coordinated spectroscopic and rapid kinetic studies of the fatty acid decarboxylase UndA. The enzyme superfamily has since been recognized to orchestrate a variety of substrate transformations for natural product biosynthesis. In this mini-review, we report on the structures and the catalytic mechanisms of the major HDO subtypes that catalyze carbon-carbon bond cleavage, N-oxygenation, multi-step rearrangements, and radical hole-hopping. A summary of the current status of the field and opportunities for decrypting the molecular basis for the mechanistic divergence of the family are highlighted.

Myoferlin, a type 2 transmembrane protein in the ferlin family, is traditionally known for its role in membrane fusion during muscle development and repair. Recent research identifies myoferlin as a potential biomarker and a critical driver of cancer progression, particularly in breast cancer and pancreatic ductal adenocarcinoma. While its lack of specificity limits its use as a biomarker, its multifaceted role in cellular membrane dynamics makes it a promising therapeutic target. In cancer cells, myoferlin regulates the recycling and stability of receptor tyrosine kinases, thereby promoting invasion and metastasis. Beyond the plasma membrane, it maintains mitochondrial homeostasis by interacting with the machinery for mitochondrial fusion and calcium exchange at the endoplasmic reticulum-mitochondria interface. Depletion of myoferlin disrupts these processes, leading to mitochondrial fragmentation, reduced ATP production, and iron-dependent cell death. Furthermore, myoferlin influences the tumour microenvironment by regulating pancreatic cancer-associated fibroblasts. It interacts with SEC24 to facilitate the coat protein complex II-mediated transport of the transforming growth factor-beta 1 receptor, driving the desmoplastic reaction and matrix protein deposition. The 'one punch-two hits' strategy-simultaneously targeting the metabolic and signalling pathways of both malignant cells and the stroma-offers a novel therapeutic perspective. The development of small molecules targeting myoferlin's C2 domains confirms its potential to reduce tumour growth and metastatic dissemination.

Amyloid fibrils formed by α-synuclein are a hallmark of a range of neurodegenerative diseases, notably Parkinson's disease, multiple system atrophy (MSA), and dementia with Lewy bodies, collectively known as synucleinopathies. Recent years have seen an increasing understanding of the structural architecture and diversity of α-synuclein amyloid fibrils. Furthermore, our mechanistic understanding of the formation of these structures has also experienced significant progress. Here, I provide a concise overview of the current state of knowledge of how α-synuclein amyloid fibrils can be amplified, i.e., increase in number. The main emphasis is thereby on the process of secondary nucleation, i.e., the generation of new amyloid fibrils catalyzed by existing fibrils. A detailed understanding of fibril amplification is relevant in the context of the spread of pathology in the central nervous system of synucleinopathy patients. In addition, it can also be exploited in the framework of diagnostic approaches collectively known as seed amplification assays (SAAs). In such assays, the minute quantities of α-synuclein fibrils present in biological fluids are amplified and possibly quantified for disease diagnostics.

Toxins, substances that are produced by living organisms with the potential to cause harm, demonstrate great diversity in their structure, function, and origin. Though some toxins have been repurposed for use as novel therapeutics, research tools, or for application in agriculture, the mechanism of action for many toxins remains uncharacterised. Pooled CRISPR screens offer a high-throughput and unbiased method for rapid annotation of the host cell genome and identification of factors mediating or modifying intoxication. In this review, we provide a brief overview of CRISPR screening before detailing how screens have been used to characterise toxins from various biological kingdoms. We highlight certain cell entry factors and intracellular processes as conserved targets of various toxins. Finally, we highlight limitations in the methods of CRISPR screens used thus far and make recommendations as to how screen design can be modified to more completely characterise toxin activity and elucidate systemic effects of intoxication.

The continuing development and characterisation of human-induced pluripotent stem cell (hiPSC)-derived cell-types has opened up a virtually endless source of human, physiologically relevant cells, available at scale, for scientific research. The technology's maturation and refinement have allowed additional cell-types and sub-types to become available. The first step in adopting these novel cell-types is to properly characterise these cells and compare how they perform against the longer-established cell-types. Parallel to the progress in iPSC-derived cells has been the great strides in the platforms developed to assess and analyse the characteristics and functions of cells. These improved platforms have greatly increased the range, throughput and quality of the functional data that can be obtained from cell-types, including iPSC-derived cells. Research into cardiomyocytes in particular has been greatly enhanced by these platforms as cardiomyocytes not only have the expected cellular markers, proteomics and transcriptomics but are also electrically active and capable of contracting, opening a wide vista of potential assays. If human iPSC-derived cardiomyocytes are to confidently replace and supplement the existing animal and cellular models of the heart, it has to be demonstrated that they correctly replicate (or even improve) upon the functions and pharmacology of the existing heart models used on these new and improved platforms. Therefore, this review compares the functional and pharmacological differences seen between Axol's human iPSC-derived atrial and ventricular cardiomyocyte cells on a range of established and newer platforms demonstrating the advantages of using chamber-specific human iPSC-derived cardiomyocytes and discussing how their use could supplement these emerging techniques.

Histones are critical for the packaging of nuclear DNA and chromatin assembly, which is facilitated by the high abundance of lysine and arginine residues within these proteins. These residues are the site of post-translational modifications, which regulate cellular processes involving DNA, such as transcription, replication, and repair. Histones are also present in the extracellular environment, following their passive release by dying cells or active release by immune cells as extracellular traps. In the extracellular environment, histones are potent antimicrobial agents and play a role in limiting the spread of infection. However, there is strong evidence that extracellular histones are also involved in propagating disease, owing to their damaging reactions with host cells. Histones are cytotoxic and pro-inflammatory and drive coagulation, which has been associated with organ failure and death in both acute and chronic inflammatory diseases. The present review describes the reactivity of histones in the extracellular environment, with a particular focus on how these reactions are influenced by post-translational modifications relevant to physiological and pathological conditions.

Transfer RNA (tRNA) is an important RNA in cells that decodes messenger RNA (mRNA) codons during protein translation to ensure correct amino acid sequences. The biogenesis of tRNA involves multiple processing steps to produce mature and functional molecules. Pseudouridine (Ψ), a derivative of uridine, is an abundant RNA modification and occurs at multiple positions within tRNAs. These modified sites are highly conserved across organisms. Classical biochemical studies have established that Ψ stabilises RNA-RNA interactions, but structural characterisations and molecular dynamics simulations reveal that Ψ can locally remodel tRNA architecture in ways that are dictated by where it is within tRNAs. Advances in transcriptome-wide Ψ mapping have uncovered additional modified sites beyond those previously described, with several novel sites appearing to be regulated in a cellular context-dependent manner. Furthermore, dysregulated pseudouridylation has been implicated in conditions ranging from cancer to inherited genetic disorders. Together, these developments reframe our understanding of Ψ from a well-established RNA stabiliser to a modification with roles far more dynamic, context-dependent, and clinically relevant than previously appreciated. The present review summarises and discusses the up-to-date developments in the impacts of pseudouridylation on human tRNA biogenesis, tRNA functions, and human health. More mechanistic questions remain open and will require further investigation. As pseudouridylation can also happen in mRNA and rRNA, exploring the interplay between these RNAs will be crucial for fundamental biology and advancing Ψ applications in biotechnology and biomedical uses.

Cancer immunotherapy, including immune checkpoint inhibitors (ICIs) and chimera-antigen receptor (CAR)-T cell therapy, has achieved substantial clinical success. However, response rates remain limited in many patients due to tumor-intrinsic immune evasion and immune cell dysfunction within the tumor microenvironment (TME). Rho family small GTPases are key signaling regulators of cytoskeletal dynamics, intracellular trafficking, transcription, and metabolism in cancers. Emerging evidence implicates Rho GTPase signaling in mediating immunotherapy efficiency through its context-dependent functions. Individual Rho GTPases modulate immunotherapy responses in tumor cells and various immune cells through actomyosin-mediated chemotaxis, cell junctions, cell polarity, and gene/epigenetic networks, among other pathways. The present review summarizes both the direct evidence linking Rho GTPases in tumor cells to immunotherapy responses and the indirect role of the selective Rho GTPase signaling network in various immune cells, with a focus on the recent progress in understanding the molecular mechanisms and associated outcomes of the ICIs and CAR-T cell therapies. We highlight current knowledge gaps at the intersection of Rho GTPase biology and cancer immunology and discuss therapeutic implications, proposing that selective modulation of specific Rho GTPase signaling pathways in tumor or TME immune cells represents a promising strategy to improve immunotherapy efficiency.

Adipose tissue is a key regulator of metabolic homeostasis; however, its dysfunction can lead to complications, including the development of metabolic disease. While mature adipocytes play an important role in this relationship, their size and buoyancy have made characterizing them difficult at the single cell level. Development of single-nuclear RNA sequencing and spatial transcriptomics have allowed for the study of mature adipocytes at unprecedented resolution and have enabled the identification of previously unappreciated subpopulations of adipocytes, some of which are associated with specific adipose depots or metabolic conditions. Here, we review the recent publications in the field and attempt to synthesize the populations identified by individual studies into classes based on their predicted functionality. We also discuss critical gaps in our current understanding of adipocyte subpopulations, including the current dearth of functional characterization of these populations.

Amyotrophic lateral sclerosis (ALS) is the most common form of adult-onset motor neuron disease, characterised by the degeneration of upper and lower motor neurons. The cytoplasmic aggregation of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein, is considered a hallmark of ALS pathology, found in nearly all postmortem cases of ALS. TDP-43 is normally primarily nuclear, where it has a widespread role in gene regulation. Mutations, extrinsic stressors, and alterations in RNA homeostasis in ALS lead to nuclear depletion of TDP-43 and the formation of cytosolic TDP-43 aggregates. This causes multiple downstream effects on neuronal function and degeneration as well as gene expression. TDP-43 is a promising target as a biomarker, as it is found to be elevated in the biofluids of ALS patients, and its cytoplasmic aggregation can also be observed in peripheral tissues; however, methodological variability and technical limitations currently preclude the establishment of TDP-43 as a standalone biomarker. There are also promising therapeutic strategies in development targeting TDP-43 pathology, but a critical challenge that remains is achieving a balance between eliminating toxic aggregates and preserving the essential functions of TDP-43. In summary, with further research, considering TDP-43 pathology in ALS gives hope for finding future novel diagnostics and therapeutics for ALS.

Calcium (Ca2+) signaling is a fundamental regulator of virtually all aspects of eukaryotic cell physiology, including gene expression, secretion, metabolism, motility, and cell fate decisions. The spatial and temporal control of cytosolic Ca2+ signals relies on a coordinated interplay between intracellular Ca2+ stores and plasma membrane (PM) Ca2+ channels. A critical advance in this field over the past two decades was the molecular identification of stromal interaction molecule 1 (STIM1) as the long-sought Ca2+ sensor that couples depletion of endoplasmic reticulum Ca2+ stores to Ca2+ influx across the PM. STIM1 has been established as a core component of store-operated Ca2+ entry, acting through direct activation of ORAI Ca2+ channels. However, accumulating evidence now indicates that STIM1 functions extend beyond this canonical role. STIM1 participates in the regulation of multiple classes of ion channels, contributes to the organization of membrane contact sites, and acts as a signaling scaffold influencing cellular processes independently of classical store depletion. This review summarizes the discovery and canonical functions of STIM1 and focuses on its emerging non-canonical roles, highlighting how STIM1 has evolved from an ER Ca2+ sensor into a multifunctional signaling hub.