搜索结果：Essays in biochemistry

The gut microbiome plays a pivotal role in host metabolic, cardiovascular, and immune health. Increasing evidence also links it to aging-associated neurocognitive decline and neurodegenerative disorders, including Alzheimer's disease (AD) and related dementias. While the precise mechanisms of the gut-microbiome-brain axis remain incompletely understood, recent findings challenge the traditional view of AD as a disease confined to the central nervous system. Aging-associated gut dysbiosis, marked by loss of beneficial microbes, expansion of opportunistic pathogens, and reduced microbial diversity, can compromise intestinal barrier integrity, leading to 'leaky gut' and increased translocation of microbial components or pathogens into the circulation. These elements may cross a weakened blood-brain barrier, triggering neuroinflammation, amyloid-beta accumulation, tau hyperphosphorylation, and neuronal injury. Such pathobiome-driven inflammatory cascades may initiate or accelerate AD pathology, shifting the etiological perspective beyond the amyloid and tau hypotheses toward systemic and peripheral contributors. Our work and others' have identified distinct dysbiotic microbiome signatures in AD, supporting the possibility that AD pathogenesis may begin in the gut. Restoring microbial homeostasis through targeted interventions could attenuate neuroinflammatory and neurodegenerative processes, offering a novel preventive and therapeutic avenue. This emerging paradigm underscores the need for comprehensive, mechanistic, and longitudinal studies to define how aging-driven microbiome alterations influence the gut-brain axis and contribute to AD progression.

Through its various roles in protein quality control, membrane dynamics, and cellular survival pathways, the AAA+ ATPase p97/valosin-containing protein emerges as a significant regulator of mitochondrial homeosta sis. This review comprehensively examines the multifaceted functions of p97 in mitochondrial biology, spanning from mitochondria-associated degradation to newly discovered functions in organellar cross-talk and disease pathogenesis. Underlying its cellular importance, p97 mutations are found in amyotrophic lateral sclerosis and frontotemporal dementia. To elucidate its mechanistic contribution to these processes, we provide a detailed table (Table 1) listing all known mitochondrial Cdc48/p97 substrates and associ ated proteins, categorized by their respective pathways. Recruitment to most of these substrates occurs by specialized adaptors, including Doa1/phospholipase A-2-activating protein, UBXD8, and UBXN1. p97 orchestrates the extraction and proteasomal degradation of outer mitochondrial membrane proteins, which are essential for maintaining mitochondrial integrity. For example, by controlling the turnover of fusion factors MFN1/2 and fission machinery, p97 regulates mitochondrial dynamics. p97 also governs apoptotic signaling through the regulated degradation of anti-apoptotic factors, such as myeloid cell leukemia-1 and VDAC, thereby modulating mitochondrial permeability. In mitophagy, p97 enables the clearance of damaged organelles by extracting ubiquitinated substrates and recruiting autophagy machinery. Beyond proteolysis, p97 facilitates recycling of endoplasmic reticulum-mitochondria contact sites through regulation of UBXD8-dependent lipid metabolism. Recent discoveries have revealed p97's involvement in pathogen host interactions and circular RNA-mediated regulation, thereby expanding our understanding of its cellular functions. The emerging picture positions p97 as an integrative hub co-ordinating mitochondrial protein homeostasis, organellar dynamics, and cell fate decisions, with therapeutic potential for metabolic and neurodegenerative disorders.

In nature, microorganisms exist in multispecies microbial communities containing bacteria, fungi, archaea, and viruses. The organisation, behaviour, and ecological impact of these communities are very much defined by the various interactions between bacteria and fungi within the community, with physical associations, chemical communication, metabolic exchange, and genetic regulation collectively shaping how these interkingdom communities assemble, adapt, and influence their hosts and habitats. Methods of interaction are widely shared across the microbiota of plants, animals, and the built environment; however, interkingdom microbial communities have environmentally specific outcomes, meaning it is critically important to understand bacterial-fungal interactions (BFIs) within the host or environmental context. With recent advances in BFI analysis now providing increasingly detailed resolution of BFIs and their function in the dialogue between interkingdom microbial communities and their growth environment, we can now gain better insight into these fundamental processes. In the present mini-review, we detail the main BFIs observed in these interkingdom microbial communities, and their implications in the context of plant, human, and the health of the built environment. We also discuss tools and methodologies for their analysis and potential use in the development of microbially derived technologies to improve health and well-being. Finally, we endorse the perspective that interkingdom microbial communities should be considered as structured, interdependent networks with analogy to multicellular organisation.

The aberrant accumulation of misfolded proteins marked by cellular dysfunction and progressive neuronal loss is the hallmark of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This review examines the pivotal role of ubiquitin modifications in altering the fate of aggregation-prone proteins such as tau, α-synuclein, mutant huntingtin, TAR DNA-binding protein 43 and superoxide dismutase 1. The ubiquitin signatures identified by their linkage types, chain architectures and site specificities emerge as a complex regulatory language that influences the clearance, aggregation or cellular propagation of these aggregating proteins. The dysregulation of other components of the ubiquitin association pathways, such as impaired E3 ligases and deubiquitinases, also contributes to the inefficient protein disposal and disease progression. Understanding how ubiquitin signatures alter the spatiotemporal dynamics of aggregating proteins is critical for advancing our knowledge of disease biology. Here, we focus on the role of ubiquitin modifications and their associated regulators affecting protein fate and neurotoxicity, and highlight the current therapeutic strategies targeting the degradation of aggregating proteins to uncover potential avenues for treating neurodegenerative diseases.

Protein degradation via the proteasome is a fundamental process for maintaining proteostasis. The post-translational modification of substrate proteins by ubiquitin and the ubiquitin-like modifier FAT10 targets them for proteasomal degradation. While ubiquitin and FAT10 have traditionally been perceived as passive signals for proteasomal targeting, emerging evidence indicates that they actively influence both the thermodynamic and conformational landscapes of their respective substrates. In this review, we explore recent mechanistic insights into how the modification site and the intrinsic characteristics of the modifier dictate substrate stability. Ubiquitin destabilizes proteins in a site-specific manner through entropic restriction or enthalpic disruption, thereby modulating degradation efficiency. It is noteworthy that well-folded ubiquitin substrates require unfoldases such as p97/valosin-containing protein for successful degradation. Conversely, FAT10 acts as a significant destabilizer across various substrates due to its inherent low thermodynamic stability and flexible structure, thereby facilitating rapid degradation independent of unfoldases. These findings redefine post-translational tagging as an active regulator of protein fate and propose novel strategies for manipulating protein turnover within disease contexts.

The gut microbiota plays a pivotal role in human health, partly through the production of bioactive metabolites from dietary tryptophan. These indole derivatives have emerged as key modulators of immune function, inflammation, and metabolic health and have been linked to various diseases. In the context of cancer, indole derivatives are increasingly being studied as promising modulators of immune checkpoint inhibitor (ICI) therapy, with accumulating evidence indicating potential for various derivatives to enhance therapeutic efficacy. ICI therapy is associated with various immune-related adverse events, including accelerated progression of atherosclerotic cardiovascular disease. Given their immunomodulatory properties, there is a growing interest in the usage of indole metabolites to mitigate these cardiovascular complications. This mini-review summarizes current knowledge on the roles of microbiota-derived indoles in cancer, ICI therapy, and atherosclerosis. Though direct evidence linking bacterial tryptophan-derived metabolites to ICI-associated atherosclerosis is currently lacking, accumulating evidence indicates that indole derivatives regulate pathways involved in both anti-tumor immunity and atherosclerosis. Advancing our understanding of how the microbiome and its metabolites influence both cancer and cardiovascular disease will be crucial for developing personalized, metabolite-based strategies to improve outcomes in patients undergoing ICI therapy.

Cancer metastasis is one of the hallmarks of cancer. This multistep process involves a cascade of alterations at the cellular and molecular level, including the epithelial-to-mesenchymal transition (EMT), invasion, migration, extracellular matrix (ECM) degradation, angiogenesis, and colonization. Expression level of critical factors associated with these processes is altered at the post-translational level through ubiquitination. Therefore, E3 ubiquitin ligases, components of the ubiquitin-mediated proteasome system, play a crucial role in controlling each step of metastasis by promoting the ubiquitination of several important factors. In this review, we have summarized the importance of E3 ligase in metastasis. Several E3 ligases act as promoters, while others act as repressors of metastasis. This article focuses on the potential role of E3 ubiquitin ligases in cancer metastasis and reveals their molecular function and targets, which are crucial for therapeutic interventions in anti-cancer therapies. Further, we covered the development of small molecule inhibitors and proteolysis-targeting chimeras to target E3 ubiquitin ligases involved in promoting metastasis for therapeutic intervention. Despite tremendous advancements, there are still many unanswered questions, especially regarding the complete characterization of the diverse range of E3 ligase functions and the conversion of preclinical discoveries into successful clinical treatments. In addition, future directions are concentrated on using technologies to develop highly specific therapeutic interventions and exploring their potential in combination with other treatment modalities, including immunotherapy, to ultimately overcome the challenges of cancer metastasis.

The ubiquitin-proteasome system (UPS) is essential for maintaining cellular proteostasis by selective proteasomal degradation of ubiquitinated proteins. Proper function of the UPS ensures turnover of proteins that have completed their role and removal of damaged proteins. Recent studies have identified p62/Sequestosome-1 as a key modulator of UPS efficiency, particularly through its ability to form dynamic, membraneless condensates via liquid-liquid phase separation. Within the nucleus, these structures recruit and concentrate components of the UPS, including its proteolytic arm - the 26S proteasome and ubiquitinated substrates. This organization enhances substrate recognition and degradation efficiency. Nuclear p62 condensates play an essential role in controlling the turnover of oncogenic proteins. Specifically, they facilitate the proteasomal degradation of the transcription factor c-Myc and prevent its nuclear accumulation by recruiting both c-Myc and its E3 ligase complex SCFFbxw7. Additionally, nuclear p62 condensates contribute to the maintenance of promyelocytic leukemia (PML) nuclear bodies and protect them from stress-induced disassembly by stabilizing the PML protein through sequestration and subsequent degradation of RING Finger Protein 4 (RNF4) - its major E3 ligase. Under stress conditions such as oxidative stress, heat shock, or DNA damage, p62 nuclear condensates rapidly assemble and recruit molecular chaperones and ubiquitin ligases, thereby promoting the clearance of misfolded and damaged proteins. Loss of nuclear p62 or disruption of its condensate-forming domains affects UPS function and compromises proteostasis. These findings highlight the role of p62 condensates in coordinating nuclear protein quality control and protecting cells from proteotoxic and oncogenic stress.

In response to soil nitrogen (N) scarcity, plants adapt through physiological plasticity and metabolic strategies that secure and conserve N. Beyond root architecture, microbial symbioses, and allelopathic inhibition of competing plants, many plant species release biological nitrification inhibitors (BNIs) from the roots that slow the microbial oxidation of ammonium to nitrate, retaining N in the root zone and improving N uptake. The diversity of BNIs spans a broad spectrum of chemical properties with highly hydrophobic molecules (e.g., sorgoleone, zeanone, brachialactone) concentrated at root-particle interfaces, while more hydrophilic or amphipathic compounds (e.g., methyl 3-(4-hydroxyphenyl) propionate, syringic acid, 6-methoxy-2-benzoxazolinone) diffuse farther into the soil, supporting spatially distributed inhibition in soil. While some of these molecules have been known for decades, their mode of action remains elusive and possibly acts through multiple targets including inhibition of key enzymes involved in microbial nitrification, namely, ammonia monooxygenase and hydroxylamine oxidoreductase, whereas others potentially chelate metal cofactors or destabilize membranes. Major gaps remain in current BNI research: most biosynthetic pathways and exudation mechanisms are unresolved, and linking BNI trait to field performance is highly dependent on soil conditions, climate variations, and microbial communities. We outline a research agenda linking enzymology, genomics, and rhizosphere ecology to decode BNI function for future breeding, engineering, or bioproduction, toward low-nitrification cropping systems.

The ubiquitin-proteasome system (UPS) represents a highly conserved protein degradation pathway that plays an essential role in maintaining the homeostasis of cellular proteins. This system ensures precise regulation of key regulators within the light signaling pathway, thereby enabling plants to dynamically switch between skotomorphogenesis (growth in the dark) and photomorphogenesis (growth in the light). In darkness, the negative E3 ligases (e.g. CRL4COP1-SPA) target photomorphogenesis-promoting regulators (e.g. ELONGATED HYPOCOTYL5) for ubiquitination and degradation, consequently repressing photomorphogenesis. Conversely, under light conditions, the positive E3 ligases (e.g. CRL1EBF1/2) promote the ubiquitination and degradation of photomorphogenesis-inhibitory regulators (e.g. phytochrome-interacting factors), ensuring proper seedling photomorphogenic development. This mini-review provides a concise overview of the ubiquitin-proteasome system in plants, focusing on recent advances in understanding the role of the UPS in regulating photomorphogenesis. Additionally, we highlight current challenges in further exploring the role of the UPS in photomorphogenesis.

The PARK2 gene, which encodes the E3 ubiquitin ligase Parkin, and the PARK6 gene, encoding phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), are frequently mutated in patients with Parkinson's disease (PD). Parkin is normally maintained in an autoinhibited conformation, and its activation is triggered by PINK1-mediated phosphorylation of both ubiquitin or NEDD8 and Parkin's ubiquitin-like (Ubl) domain. This review provides a comprehensive overview of the models proposed over the past decade to explain Parkin's autoinhibition and activation. We summarize key structural and biophysical studies that have progressively uncovered the molecular basis of Parkin activation, tracing the evolution of these insights. This review concludes by discussing the intriguing and still unresolved question of whether Parkin activation occurs through a cis or trans mechanism and outlines future directions for research aimed at understanding these pathways.

Although some microbial compounds have been repurposed for human use, microorganisms did not evolve their specialised metabolites with us in mind. Many natural products likely possess hidden activities, while others may be exploited in ways that ignore their most biologically relevant roles. Uncovering the true function of these compounds is essential not only for understanding microbial interactions in native environments but also for unlocking their most appropriate use. To facilitate prioritisation in discovering new natural products, computational tools have been developed to predict the function of compounds hidden in cryptic biosynthetic gene clusters. Yet beyond in silico predictions, understanding when, where, and why metabolites are produced is critical for both fundamental biology and targeted discovery. After all, what nature chooses to activate at a specific time or condition tells us what it is really for. Based on the principle 'function follows regulation', it is no coincidence that expression of metal chelators, phytotoxins, pigments, and antibiotics is controlled by metal availability, plant byproducts, radiations, and competitor sensing, respectively. Likewise, metabolite localisation and production timing also provide clues to function such as intracellular antiproliferative agents coordinating programmed cell death or pigments protecting against oxidative stress. These controlled expression patterns suggest a strategic approach for natural product discovery: focusing on culture conditions that mimic the environmental or developmental contexts under which metabolites are needed for the producer. Integrating expression control information offers a predictive framework to guide experimental design, increases the likelihood of identifying compounds with meaningful ecological roles, and anticipates their applications.

Transposon mutagenesis has re-emerged as a powerful and versatile strategy for discovering and characterising specialised metabolites encoded by biosynthetic gene clusters (BGCs). While genomics has revealed an enormous diversity of putative BGCs across bacteria, many remain silent, weakly expressed, or genetically intractable, necessitating experimental tools that can link genotype to chemical output. Transposons provide an unbiased and broadly applicable platform for disrupting, activating, or modulating gene expression without relying on homologous recombination, making them particularly valuable in challenging microbial hosts. Here, we review the major applications of transposon mutagenesis in natural product discovery, providing examples that highlight discoveries made using phenotype- and bioactivity-guided screens, phenotype-independent strategies, and transposon-based engineering of heterologous expression platforms. Transposon technologies provide flexible and scalable tools for activating, characterising, and engineering microbial BGCs. As genome mining continues to unearth rich seams of unexplored metabolic potential, these tools will remain essential for converting genetic predictions into chemical discovery.

SUMOylation, a protein post-translational modification (PTM) involving the covalent attachment of small ubiquitin-like modifier (SUMO), regulates a wide range of cellular processes. The key hallmark of SUMO that distinguishes it from ubiquitin is the hydrophobic groove that binds short linear motifs known as SUMO-interacting motifs (SIMs), which are found across a broad spectrum of partners, including SUMO E3 ligases and downstream effector proteins such as transcription factors, DNA-repair proteins, ubiquitin E3 ligases and cell-signalling components. In addition, various effectors interacting in a SIM-independent manner have been reported. In this review, we summarise the current understanding of non-covalent SUMO interactions mediated by SIMs and other, alternative SUMO-binding elements. Focusing on the evolution and structural basis of these interactions, we discuss the methodological approaches used in the field, outline emerging mechanisms and concepts and highlight key open questions.

Ubiquitination is a fundamental post-translational modification that orchestrates a wide range of cellular processes. This modification is executed through a cascade of enzymatic steps involving E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. Among these, E2 enzymes and specific E3 ligases primarily dictate the type of ubiquitin linkage formed. Ubiquitination system can form chains of ubiquitin on any of its seven lysine residues or its N-terminal methionine, each generating a distinct three-dimensional topology. These structurally diverse polyubiquitin chains are selectively recognized by ubiquitin receptors, influencing substrate stability, localization, and interactions. These topologically diverse polyubiquitin chains function as discrete molecular signals, each with distinct physiological outcomes. This review focuses on key developments in our understanding of how specific ubiquitin linkage types participate in various cellular pathways and their implications on the fate and function of the protein.

The present essay attempts to stimulate interest and provide insight into the dynamics of internal conflicts, kin selection, and ecological interactions in multicellular, metabolically gifted microorganisms and how these processes may affect biosynthetic gene cluster (BGC) diversity. The multicellular antibiotic-producing soil bacterium Streptomyces provides a useful model for exploring how internal conflicts emerge and are resolved in biology. These organisms must balance two resource-intensive processes that can create internal conflicts-natural product biosynthesis and sporulation. In Streptomyces, there is potential to mitigate these internal conflicts through division of labour, phenotypic specialisation, and extensive gene duplication and diversification, enabling colonies to optimise both natural product production and reproductive success. Horizontal gene transfer further expands gene families and BGCs, introducing new metabolic capabilities while generating opportunities for functional divergence to reduce internal conflict and potentially promote kin selection. Natural product BGCs also possess features that could identify them as 'greenbeards' (kin selection by trait), promoting cooperation among producers and harming non-producers. The coexistence of multiple natural product BGCs and resistance mechanisms in Streptomyces is discussed in the context of the diverse eco-evolutionary processes occurring in structured natural environments, competition among close relatives, recurrent BGC acquisition, and regulatory compatibility encountered by Streptomyces.

The optical microscope has served as an essential tool for the microbiologist since van Leeuwenhoek's observations of 'animalcules', yet the core design of the objective lens has changed little over the last 100 years and imparts a dichotomy between resolution and field of view. High numerical aperture objectives resolve subcellular detail but sample only small regions, whereas low-magnification objectives capture large areas with limited resolving power. Many microbial processes span the micron-to-centimetre length scales, constraining how spatial heterogeneity, microbial interaction, and rare events can be visualised in intact specimens. This review describes how the Mesolens overcomes this limitation by combining low magnification with high numerical aperture to deliver sub-micron resolution across multi-millimetre fields of view and millimetre-scale depths. We summarise the optical principles and imaging modalities that underpin the Mesolens, including widefield and confocal laser scanning mesoscopy, and emerging implementations such as light-sheet mesoscopy, mesoscopic total internal reflection fluorescence, and standing-wave mesoscopy. We highlight applications where spatial context is essential; the discovery and characterisation of biofilm nutrient transport channels in Escherichia coli, understanding the architecture of cross-kingdom Candida albicans-Staphylococcus aureus biofilms, and translational applications in clinical and environmental microbiology. Finally, we discuss specimen preparation, analysis workflows, and future opportunities in new modalities, computationally guided acquisition, and scalable optical manufacturing. Together, these advances position the Mesolens as a versatile tool to resolve microbial interactions and dynamics across length scales associated with priority areas in microbiology.

Antimicrobial resistance (AMR) is a growing global health crisis, with mortality already in the millions and projections of up to 10 million deaths annually by 2050. Traditional discovery strategies, such as one strain many compounds-based screening of large strain collections, have yielded most of our current antibiotics but are slow, resource-intensive, and highly prone to rediscovery. In parallel, high-throughput sequencing has uncovered an enormous reservoir of biosynthetic gene clusters (BGCs), of which only a small fraction has been experimentally characterized, and many show extensive overlap in gene content. This combination of hidden diversity and functional redundancy demands new tools to prioritize, monitor, and rationally activate BGCs. In this review, we discuss how biosensors can be integrated with genome mining to accelerate antimicrobial discovery and BGC dereplication. We summarize the chemical scaffolds, biosynthetic logic and diagnostic enzymatic signatures of major antimicrobial classes, including β-lactams, tetracyclines, macrolides, aminoglycosides, glycopeptides, lincosamides, polyenes, and azoles, and highlighting representative biosensors that target each scaffold. The biosensors discussed use transcription factors, enzymes, aptamers, CRISPR systems and stress-response modules to generate specific and sensitive signals in complex matrices. We argue that translating BGC architecture into biosensor design creates a practical framework to rapidly discriminate from novel activities, but most importantly, to guide the exploration of chemical space around clinically important scaffolds in the era of escalating AMR.

Seed priming is a common approach to improve germination and seedling stress tolerance. Most priming treatments involve imbibition of seeds in water or in solutions of different chemicals, followed by redrying seed before the completion of germination. Physical priming treatments based on various forms of radiation or non-thermal plasma, for example, are also possible. Physical priming has some advantages over imbibition-based priming treatments, including avoiding negative impacts on the longevity of primed seed. Physical priming has potential for applications in agriculture, but questions remain about mechanisms of action and the range of outcomes generated by different types of treatment. Here, we suggest potential mechanisms by which physical treatments might impact the future performance of seeds and seedlings, including physiochemical modifications of the seed coat, generation of reactive oxygen species, and DNA-damage responses. In particular, we discuss how biological responses may be triggered by treatment of dry seeds that lack significant metabolic activity. We also briefly consider downstream molecular and biochemical responses to physical priming in germinating seeds. We conclude our review by briefly reflecting on key steps required for effective commercial exploitation.