Biochemical Society Transactions[JOURNAL]
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200 papers
CRAC channels and patho-physiology of peripheral organ systems.
Bhardwaj R, Parekh AB
Biochem Soc Trans · 2025 Jun · PMID 40459545 · Full text
A rise in cytosolic Ca2+ is used as a key signalling messenger in eukaryotic cells. The Ca2+ signal drives life and death and controls myriad responses in between. Inherent in the use of such a multifarious signal is the...
A rise in cytosolic Ca2+ is used as a key signalling messenger in eukaryotic cells. The Ca2+ signal drives life and death and controls myriad responses in between. Inherent in the use of such a multifarious signal is the danger of disease, arising from dysregulated Ca2+ signalling. One ancient, highly conserved and widespread Ca2+ entry pathway is the store-operated Ca2+ release-activated Ca2+ (CRAC) channel. Mutations in STIM1 and ORAI1, the genes that encode the functional channel, are tightly linked to a CRAC channelopathy in humans, which encompasses severe combined immune deficiency, myopathy and anhidrotic ectodermal dysplasia. Moreover, sustained Ca2+ entry through the channels leads to a range of systemic disorders, including acute pancreatitis, asthma and inflammatory bowel disease. In this review, we describe how aberrant CRAC channel activity causes a range of diseases, highlighting commonalities between these diverse pathologies.
Mechanisms of heme transport in the mitochondria.
Ali SF, White AE, Medlock A … +1 more , Khalimonchuk O
Biochem Soc Trans · 2025 Jun · PMID 40440032 · Full text
Heme is a vital but highly reactive compound that is synthesized in mitochondria and subsequently distributed to a variety of subcellular compartments for utilization. The transport of heme is essential for normal cellul...
Heme is a vital but highly reactive compound that is synthesized in mitochondria and subsequently distributed to a variety of subcellular compartments for utilization. The transport of heme is essential for normal cellular metabolism, growth, and development. Despite the vital importance of heme transport within the cell, data are lacking about how newly synthesized heme is shuttled within the mitochondrion or exported from the organelle. Here, we briefly summarize current knowledge about the process of mitochondrial heme distribution and discuss the current unresolved questions pertinent to this process.
Insights into the role of collided ribosomes during the activation of the integrated stress response.
Nanjaraj Urs AN, Kim L, Zaher HS
Biochem Soc Trans · 2025 Jun · PMID 40440025 · Full text
Mechanisms that regulate and reprogram gene expression are particularly important under stress conditions. The integrated stress response (ISR) signaling pathway is one such pro-survival and adaptive mechanism conserved...
Mechanisms that regulate and reprogram gene expression are particularly important under stress conditions. The integrated stress response (ISR) signaling pathway is one such pro-survival and adaptive mechanism conserved in eukaryotes. The ISR is characterized by the activation of protein kinases that phosphorylate the eukaryotic initiation factor 2α (eIF2α) in response to several stress conditions, including nutrient deprivation, viral infection, and protein misfolding. Phosphorylation of eIF2α results in global inhibition of translation, while promoting the translation of a few pro-survival genes. Here, we focus on the mechanism of activation of the eIF2α kinase general control nonderepressible 2 (Gcn2). The protein was initially discovered in yeast more than four decades ago, and it was proposed to respond to amino acid starvation through the accumulation of deacylated tRNAs. However, more recent studies have changed our understanding of its activation and suggest a direct role for ribosome stalling and collisions in the process. In this review, we discuss the classical model for the tRNA-mediated activation of GCN2 and the recent shift in this model to accommodate the observations that wide-ranging translational stresses trigger its activation.
Exploring the interaction dynamics of eukaryotic translation initiation factor 2.
Marintchev A
Biochem Soc Trans · 2025 Jun · PMID 40411218 · Full text
Eukaryotic translation initiation typically involves recruitment of the 43S ribosomal pre-initiation complex (PIC) to the 5'-end of the mRNA to form the 48S PIC, followed by scanning in search of a start codon in a favor...
Eukaryotic translation initiation typically involves recruitment of the 43S ribosomal pre-initiation complex (PIC) to the 5'-end of the mRNA to form the 48S PIC, followed by scanning in search of a start codon in a favorable nucleotide complex. The start codon is recognized through base-pairing with the anticodon of the initiator Met-tRNAi. The stringency of start codon selection controls the probability of initiation from a start codon in a suboptimal nucleotide context. Met-tRNAi itself is recruited to the 43S PIC by the eukaryotic translation initiation factor 2 (eIF2), in the form of the eIF2-GTP•Met-tRNAi ternary complex (TC). GTP hydrolysis by eIF2, promoted by its GTPase-activating protein eIF5, leads to the release of eIF2-GDP from the PIC. Recycling of eIF2-GDP to TC is promoted by the guanine nucleotide exchange factor eIF2B. Its inhibition by a number of stress factors triggers the integrated stress response (ISR). This review describes the recent advances in elucidating the interactions of eIF2 and its partners, with an emphasis on the timing and dynamics of their binding to, and release from the PIC. Special attention is given to the regulation of the stringency of start codon selection and the ISR. The discussion is mostly limited to translation initiation in mammals and budding yeast.
Insights into the synchronization between DNA replication and parental histone recycling.
Tang X, Yao Y, Li G … +1 more , Gan H
Biochem Soc Trans · 2025 Jun · PMID 40380884 · Full text
Accurate parental histone recycling is of pivotal importance in epigenetic inheritance. Its proper functioning hinges on the precise co-ordination among a diverse array of proteins. During DNA replication, any aberration...
Accurate parental histone recycling is of pivotal importance in epigenetic inheritance. Its proper functioning hinges on the precise co-ordination among a diverse array of proteins. During DNA replication, any aberration in the distribution of parental histones can potentially result in the loss of epigenetic memory. To date, although several key proteins involved in parental histone recycling have been identified, the detailed molecular mechanisms underlying their functions remain elusive. This mini-review focuses on summarizing the synchrony between DNA replication and parental histone recycling, along with the key participants in parental histone recycling. In the end, we provide an overview of the inherent connection between parental histone recycling and epigenetic inheritance, shedding light on the fundamental role of histone recycling in maintaining epigenetic information across cell divisions.
Emerging tools and methods to study cell signalling mediated by branched ubiquitin chains.
McFarland MR, Kulathu Y
Biochem Soc Trans · 2025 Jun · PMID 40380883 · Full text
Branched ubiquitin chains are complex molecular structures in which two or more ubiquitin moieties are attached to distinct lysine residues of a single ubiquitin molecule within a polyubiquitin chain. These bifurcated ar...
Branched ubiquitin chains are complex molecular structures in which two or more ubiquitin moieties are attached to distinct lysine residues of a single ubiquitin molecule within a polyubiquitin chain. These bifurcated architectures significantly expand the signalling capacity of the ubiquitin system. Although branched chains constitute a substantial fraction of cellular polyubiquitin, their biological functions largely remain enigmatic due to their complex nature and the associated technical challenges of studying them. Recent technological innovations have enabled the identification of key molecular players and revealed essential roles for branched chains in diverse cellular processes. In this review, we discuss the bespoke strategies that have driven these discoveries, as well as the technologies needed to advance this rapidly evolving field.
Advances in ribosome profiling technologies.
Tomuro K, Iwasaki S
Biochem Soc Trans · 2025 Jun · PMID 40380882 · Full text
Ribosome profiling (or Ribo-seq) has emerged as a powerful approach for revealing the regulatory mechanisms of protein synthesis, on the basis of deep sequencing of ribosome footprints. Recent innovations in Ribo-seq tec...
Ribosome profiling (or Ribo-seq) has emerged as a powerful approach for revealing the regulatory mechanisms of protein synthesis, on the basis of deep sequencing of ribosome footprints. Recent innovations in Ribo-seq technologies have significantly enhanced their sensitivity, specificity, and resolution. In this review, we outline emerging Ribo-seq derivatives that overcome barriers in low inputs, rRNA contamination, data calibration, and single-cell applications. These advances enable detailed insights into translational control across diverse biological contexts.
Advances in understanding the mechanisms of the human papillomavirus oncoproteins.
Obanya DI, Wootton LM, Morgan EL
Biochem Soc Trans · 2025 Jun · PMID 40380881 · Full text
High-risk human papillomaviruses (HPVs) are responsible for almost all cervical cancer cases and a growing number of oropharyngeal and anogenital cancers. The primary HPV oncoproteins, E6 and E7, act together to manipula...
High-risk human papillomaviruses (HPVs) are responsible for almost all cervical cancer cases and a growing number of oropharyngeal and anogenital cancers. The primary HPV oncoproteins, E6 and E7, act together to manipulate multiple cellular pathways that can ultimately result in malignant transformation. This includes the deregulation of several signalling pathways that regulate cell proliferation, cell cycle progression and cell survival. Although multiple functions of HPV E6 and E7 in driving oncogenesis are well known, recent studies have uncovered novel oncogenic functions of the HPV oncoproteins, including the manipulation of emerging mechanisms of cancer development, such as epigenetic modifications, cellular plasticity and genomic instability. This review explores current advances in understanding how the HPV oncoproteins interact with these cellular processes, highlighting potential therapeutic targets in HPV-associated cancers.
Extracellular membrane particles en route to the nucleus - exploring the VOR complex.
Lorico A, Santos MF, Karbanová J … +1 more , Corbeil D
Biochem Soc Trans · 2025 Jun · PMID 40366329 · Full text
Intercellular communication is an essential hallmark of multicellular organisms for their development and adult tissue homeostasis. Over the past two decades, attention has been focused on communication mechanisms based...
Intercellular communication is an essential hallmark of multicellular organisms for their development and adult tissue homeostasis. Over the past two decades, attention has been focused on communication mechanisms based on various membrane structures, as illustrated by the burst of scientific literature in the field of extracellular vesicles (EVs). These lipid bilayer-bound nano- or microparticles, as vehicle-like devices, act as regulators in various biological and physiological processes. When EVs are internalized by recipient cells, their membrane and cytoplasmic cargoes can interfere with cellular activities, affecting pathways that regulate cell proliferation, differentiation, and migration. In cancer, EVs can transfer oncogenic factors, stimulate neo-angiogenesis and immunosuppression, reprogram stromal cells, and confer drug resistance traits, thereby remodeling the surrounding microenvironment. Although the mechanisms underlying EV biogenesis and uptake are now better understood, little is known about the spatiotemporal mechanism(s) of their actions after internalization. In this respect, we have shown that a fraction of endocytosed EVs reaches the nuclear compartment via the VOR (VAP-A-ORP3-Rab7) complex-mediated docking of late endosomes to the outer nuclear membrane in the nucleoplasmic reticulum, positioning and facilitating the transfer of EV cargoes into the nucleoplasm via nuclear pores. Here, we highlight the EV heterogeneity, the cellular pathways governing EV release and uptake by donor and recipient cells, respectively, and focus on a novel intracellular pathway leading to the nuclear transfer of EV cargoes. We will discuss how to intercept it, which could open up new avenues for clinical applications in which EVs and other small extracellular particles (e.g., retroviruses) are implicated.
Cdk activation by phosphorylation: linking growth signals to cell cycle control.
Blank HM, No EG, Polymenis M
Biochem Soc Trans · 2025 May · PMID 40358525 · Full text
Cells adjust their proliferation in response to extrinsic factors and nutrients. Such inputs must reach the cell cycle machinery to ensure proper cell proliferation. This minireview focuses on evidence suggesting that ph...
Cells adjust their proliferation in response to extrinsic factors and nutrients. Such inputs must reach the cell cycle machinery to ensure proper cell proliferation. This minireview focuses on evidence suggesting that phosphorylating the T-loop domain of cyclin-dependent kinases may be a critical and conserved conduit for these external signals. Understanding this regulatory mechanism could provide crucial insights into how all eukaryotic cells integrate external information to decide whether or not to divide.
Functions and mechanisms of eukaryotic RNA-guided programmed DNA elimination.
Stefanov BA, Nowacki M
Biochem Soc Trans · 2025 Apr · PMID 40305257 · Full text
Many eukaryotic organisms, from ciliates to mammals, employ programmed DNA elimination during their postmeiotic reproduction. The process removes specific regions from the somatic DNA and has broad functions, including t...
Many eukaryotic organisms, from ciliates to mammals, employ programmed DNA elimination during their postmeiotic reproduction. The process removes specific regions from the somatic DNA and has broad functions, including the irreversible silencing of genes, sex determination, and genome protection from transposable elements or integrating viruses. Multiple mechanisms have evolved that explain the sequence selectivity of the process. In some cases, the eliminated sequences lack centromeres and are flanked by conserved sequence motifs that are specifically recognized and cleaved by designated nucleases. Upon cleavage, all DNA fragments that lack centromeres are lost during the following mitosis. Alternatively, specific sequences can be destined for elimination by complementary small RNAs (sRNAs) as in some ciliates. These sRNAs enable a PIWI-mediated recruitment of chromatin remodelers, followed up by the precise positioning of a cleavage complex formed from a transposase like PiggyBac or Tc1. Here, we review the known molecular interplay of the cellular machinery that is involved in precise sRNA-guided DNA excision, and additionally, we highlight prominent knowledge gaps. We focus on the modes through which sRNAs enable the precise localization of the cleavage complex, and how the nuclease activity is controlled to prevent off-target cleavage. A mechanistic understanding of this process could enable the development of novel eukaryotic genome editing tools.
S-acylation in apoptotic and non-apoptotic cell death: a central regulator of membrane dynamics and protein function.
Manhertz-Patterson R, Atilla-Gokcumen GE
Biochem Soc Trans · 2025 Apr · PMID 40304073 · Full text
Protein lipidation is a collection of important post-translational modifications that modulate protein localization and stability. Protein lipidation affects protein function by facilitating interactions with cellular me...
Protein lipidation is a collection of important post-translational modifications that modulate protein localization and stability. Protein lipidation affects protein function by facilitating interactions with cellular membranes, changing the local environment of protein interactions. Among these modifications, S-acylation has emerged as a key regulator of various cellular processes, including different forms of cell death. In this mini-review, we highlight the role of S-acylation in apoptosis and its emerging contributions to necroptosis and pyroptosis. While traditionally associated with the incorporation of palmitic acid (palmitoylation), recent findings indicate that other fatty acids can also participate in S-acylation, expanding its functional repertoire. In apoptosis, S-acylation influences the localization and function of key regulators such as Bcl-2-associated X protein and other proteins modulating their role in mitochondrial permeabilization and death receptor signaling. Similarly, in necroptosis, S-acylation of mixed lineage kinase domain-like protein (MLKL) with palmitic acid and very long-chain fatty acids enhances membrane binding and membrane permeabilization, contributing to cell death and inflammatory responses. Recent studies also highlight the role of S-acylation in pyroptosis, where S-acylated gasdermin D facilitates membrane localization and pore assembly upon inflammasome activation. Blocking palmitoylation has shown to suppress pyroptosis and cytokine release, reducing inflammatory activity and tissue damage in septic models. Collectively, these findings underscore S-acylation as a shared and important regulatory mechanism across cell death pathways affecting membrane association of key signaling proteins and membrane dynamics, and offer insights into the spatial and temporal control of protein function.
Correction: Exploring the influence of anionic lipids in the host cell membrane on viral fusion.
Biochem Soc Trans · 2025 Apr · PMID 40298403 · Full text
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How do spherical bacteria regulate cell division?
Ramos-León F, Ramamurthi KS
Biochem Soc Trans · 2025 Apr · PMID 40259574 · Full text
Many bacteria divide by binary fission, producing two identical daughter cells, which requires proper placement of the division machinery at mid-cell. Spherical bacteria (cocci) face unique challenges due to their lack o...
Many bacteria divide by binary fission, producing two identical daughter cells, which requires proper placement of the division machinery at mid-cell. Spherical bacteria (cocci) face unique challenges due to their lack of natural polarity. In this review, we compile current knowledge on how cocci regulate cell division, how they select the proper division plane, and ensure accurate Z-ring positioning at mid-cell. While Streptococcus pneumoniae and Staphylococcus aureus are the most well-studied models for cell division in cocci, we also cover other less-characterized cocci across different bacterial groups and discuss the conservation of known Z-ring positioning mechanisms in these understudied bacteria.
Manipulation of targeted protein degradation in plant biology.
Rojas-Pierce M, Bednarek SY
Biochem Soc Trans · 2025 Apr · PMID 40209052 · Full text
Inducible protein degradation systems are an important but untapped resource for the study of protein function in plant cells. Unlike mutagenesis or transcriptional control, regulated degradation of proteins of interest...
Inducible protein degradation systems are an important but untapped resource for the study of protein function in plant cells. Unlike mutagenesis or transcriptional control, regulated degradation of proteins of interest allows the study of the biological mechanisms of highly dynamic cellular processes involving essential proteins. While systems for targeted protein degradation are available for research and therapeutics in animals, there are currently limited options in plant biology. Targeted protein degradation systems rely on target ubiquitination by E3 ubiquitin ligases. Systems that are available or being developed in plants can be distinguished primarily by the type of E3 ubiquitin ligase involved, including those that utilize Cullin-RING ligases, bacterial novel E3 ligases, and N-end rule pathway E3 ligases, or they can be controlled by proteolysis targeting chimeras. Target protein ubiquitination leads to degradation by the proteasome or targeting to the vacuole, with both pathways being ubiquitous and important for the endogenous control of protein abundance in plants. Targeted proteolysis approaches for plants will likely be an important tool for basic research and to yield novel traits for crop biotechnology.
Spo11: from topoisomerase VI to meiotic recombination initiator.
Harper JA, Brown GGB, Neale MJ
Biochem Soc Trans · 2025 Apr · PMID 40181639 · Full text
Meiotic recombination is required to break up gene linkage and facilitate faithful chromosome segregation during gamete formation. By inducing DNA double-strand breaks, Spo11, a protein that is conserved in all meiotic o...
Meiotic recombination is required to break up gene linkage and facilitate faithful chromosome segregation during gamete formation. By inducing DNA double-strand breaks, Spo11, a protein that is conserved in all meiotic organisms, initiates the process of recombination. Here, we chart the evolutionary history of Spo11 and compare the protein to its ancestors. Evolving from the A subunit of archaeal topoisomerase VI (Topo VI), a heterotetrameric type II topoisomerase, Spo11 appears to have evolved alongside meiosis and been present in the last eukaryotic common ancestor. There are many differences between Spo11 and TopVIA, particularly in regulation, despite similarities in structure and mechanism of action. Critical to its function as an inducer of recombination, Spo11 has an apparently amputated activity that, unlike topoisomerases, does not re-seal the DNA breaks it creates. We discuss how and why Spo11 has taken its path down the tree of life, considering its regulation and its roles compared with those of its progenitor Topo VI, in both meiotic and non-meiotic species. We find some commonality between different forms and orthologs of Spo11 in different species and touch upon how recent biochemical advances are beginning to finally unlock the molecular secrets hidden within this fundamental yet enigmatic protein.
Insights into non-proteinaceous ubiquitination.
Dearlove EL, Huang DT
Biochem Soc Trans · 2025 Apr · PMID 40181599 · Full text
Ubiquitination plays a key role in the regulation of numerous diverse cellular functions. This process involves the covalent attachment of ubiquitin to protein substrates by a cascade of enzymes. In recent years, various...
Ubiquitination plays a key role in the regulation of numerous diverse cellular functions. This process involves the covalent attachment of ubiquitin to protein substrates by a cascade of enzymes. In recent years, various non-proteinaceous substrates of ubiquitination have been discovered, expanding the potential for the functions of ubiquitination beyond its conventional role as a post-translational modification. Here, we profile the non-proteinaceous substrates of ubiquitination reported to date, the enzymes that regulate these activities, and the mechanistic details of substrate modification. The biological functions linked to these modifications are discussed, and finally, we highlight the challenges hindering further progress in the identification and functional characterization of non-proteinaceous substrates of ubiquitination within cellular contexts.
Tetraspanins affect membrane structures and the trafficking of molecular partners: what impact on extracellular vesicles?
Rubinstein E, Théry C, Zimmermann P
Biochem Soc Trans · 2025 Mar · PMID 40135387 · Full text
Tetraspanins are a family of 33 proteins in mammals believed to play a crucial role in the compartmentalization of various associated proteins within cells and membranes. Recent studies have elucidated the structure of s...
Tetraspanins are a family of 33 proteins in mammals believed to play a crucial role in the compartmentalization of various associated proteins within cells and membranes. Recent studies have elucidated the structure of several tetraspanin members, revealing that while the four transmembrane domains typically adopt a cone-shaped configuration in crystals, other conformations are also possible. This cone-shaped structure may explain why tetraspanins are often enriched in curved and tubular cellular structures, such as microvilli, tunneling nanotubes, retraction fibers, or at the site of virus budding, and may contribute to the formation or maintenance of these structures. Tetraspanins have also been detected on midbody remnants and migrasomes, as well as on extracellular vesicles (EVs), for which CD9, CD81, and CD63 are widely used as markers. Although their impact on certain membrane structures and their ability to regulate the function and trafficking of associated proteins would suggest a potential role of tetraspanins either in EV formation or in regulating their protein composition, or both, efforts to characterize these roles have been complicated by conflicting results. In line with the interaction of certain tetraspanins with cholesterol, two recent studies have suggested that the presence or organization of oxysterols and cholesterol in EVs may be regulated by Tspan6 and CD63, respectively, paving the way for further research on the influence of tetraspanins on the lipid composition of EVs.
Chlamydia trachomatis invasion: a duet of effectors.
Zimmerman TJ, Carabeo RA
Biochem Soc Trans · 2025 Mar · PMID 40131835 · Full text
Members of the genus Chlamydia require an intracellular niche for growth and replication, thus highlighting the extreme significance of its ability to invade epithelial cells-the favored host cell in vivo. Because epithe...
Members of the genus Chlamydia require an intracellular niche for growth and replication, thus highlighting the extreme significance of its ability to invade epithelial cells-the favored host cell in vivo. Because epithelial cells are not phagocytic, the uptake of Chlamydia must be driven by the pathogen. To this end, two bacterial proteins, translocated actin-recruiting protein (TarP) and translocated membrane effector A (TmeA), identified in Chlamydia trachomatis are translocated from the infectious chlamydial elementary bodies to the host cell cytosol to facilitate extensive remodeling of the cortical actin network to produce protrusive structures designed for pathogen engulfment. Notably, both effectors act by promoting highly localized actin nucleation at sites of bacterial adhesion. However, they have non-redundant functions, with both required for optimal actin remodeling dynamics and efficient invasion. Finally, these effectors also mediate the latter stages of the invasion process, specifically by modulating host dynamin 2, a large GTPase critical to closure and scission of invaginating vesicles harboring elementary bodies. In summary, TarP and TmeA orchestrate major aspects of C. trachomatis invasion.
How similar are the molecular mechanisms of yeast and metazoan genome replication initiation?
Palm G, Costa A
Biochem Soc Trans · 2025 Mar · PMID 40052964 · Full text
DNA replication start sites are licensed for replication when two hexameric ring-shaped motors of the replicative helicase are loaded as an inactive double hexamer around duplex DNA. Activation requires untwisting of the...
DNA replication start sites are licensed for replication when two hexameric ring-shaped motors of the replicative helicase are loaded as an inactive double hexamer around duplex DNA. Activation requires untwisting of the double helix and ejection of one DNA strand from the central channel of each helicase ring. The process of replication initiation is best understood in yeast, thanks to reconstitution with purified yeast proteins, which allowed systematic structural analysis of the replication initiation process. Orthologs of most yeast replication factors have been identified in higher eukaryotes; however, reconstitution of metazoan replication initiation is still in its infancy, with double hexamer loading but not activation having been achieved. Nonetheless, artificial intelligence-driven structure prediction and cryo-EM studies on native complexes, combined with cell-based and cell-free approaches, are starting to provide insights into metazoan replication initiation mechanisms. Here, we describe the emerging picture.
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