Critical Reviews in Biochemistry and Molecular Biology最新文献

The ESCRT-III complex is a highly conserved membrane remodeling system known for its essential roles in eukaryotic cellular processes such as endosomal trafficking, multivesicular body (MVB) formation, viral budding, membrane repair, and cytokinesis. These activities are critical for maintaining cellular integrity, and dysfunction in ESCRT-III has been linked to diseases including cancer, viral infection, and neurodegeneration. Recent findings suggest that bacterial homologs such as IM30 and PspA-while structurally simpler-exhibit remarkable functional similarities to their eukaryotic counterparts and play essential roles in membrane remodeling and deformation, particularly under environmental stress. However, the precise mechanisms driving these biological processes remain unclear. This review explores their structural dynamics, membrane-binding behavior, and remodeling activities. Emerging in vitro evidence suggests that PspA and IM30 assemble into high-molecular-weight oligomeric rings and filamentous structures, facilitating membrane interactions and remodeling. In contrast to eukaryotic ESCRT-III, which requires accessory proteins to form functional remodeling complexes, bacterial ESCRT-III proteins are capable of remodeling membranes autonomously. These activities drive a variety of structural transformations, including membrane curvature, elongation, protrusion, double-membrane vesicles (DMVs) formation, and fusion. By integrating recent findings, this review provides a comprehensive overview of current knowledge and highlights key directions for future research into the mechanisms and physiological roles of bacterial ESCRT-III.

Plants have been a part of human health since our very beginnings, and many of our modern pharmaceuticals claim their origins from medicinal plants. The range of specialized metabolites synthesized by plants is highly diverse, and metabolic functions have developed over the millennia to cover roles such as defense, adaptation to environmental stress, and even reproduction. These metabolites subsequently play roles in human health and diseases that are both significant and profound. The importance of plant natural products for the pharmaceutical, cosmetic and nutraceutical industries cannot be overstated. However, the fact that these specialized metabolites may be available only in low quantities from plants that are slow growing, endangered, or from fragile environments due to certain biotic and abiotic stresses makes their commercial use challenging despite the scenario that some stresses can enhance the production of secondary metabolites. Genome editing is a technique or technology that comprises of tools like CRISPR/Cas9, TALEN, ZFN. The following review describes the successful use of CRISPR/Cas9 genome editing in engineering medicinal plants, food crops and commercial crops to modulate metabolic pathways involved in the biosynthesis of valuable compounds to improve natural product identification, development and ultimately, commercial viability.

More than 170 distinct RNA modifications have been identified, playing pivotal roles in regulating development, homeostasis, and adaptive evolution. A recent groundbreaking study in Nature revealed that glycoRNA prevents endogenous RNA from being misidentified as non-self, thereby averting autoimmune responses. This function is astonishingly parallel to that of A-to-I RNA editing, another prevalent RNA modification. Here, we synthesize current knowledge of RNA modifications linked to immune function and highlight an intriguing but intuitive principle: modifications that act within the cell, such as A-to-I editing, must be installed in the nucleus before reaching the cytoplasm where unmodified exogeneous RNAs also prevail. By contrast, glycoRNA, which functions at the cell surface, faces no such spatial constraint, as self/non-self-identity needs not be resolved in the cytoplasm. We also acknowledge the existence of modifications such as C-to-U editing that appear less related to immunity. Future investigations will determine whether immune-associated functions are a dominant property of a broader spectrum of RNA modifications. Overall, this work deepens our understanding of how RNA modifications shape immune homeostasis and self/non-self-discrimination, and prompts broader reflection on how multilayered molecular regulations allow organisms to balance stability with diversity across development, evolution, and adaptation.

Targeted protein degradation is an elegant therapeutic strategy that harnesses the cell's own degradation machinery to selectively eliminate target proteins. This approach marks a paradigm shift in drug discovery, moving beyond traditional occupancy-based inhibition toward target degradation, thereby silencing proteins that have historically resisted pharmacological intervention. Degrader molecules function by inducing proximity between target proteins and effectors, most commonly E3 ubiquitin ligases, triggering their ubiquitylation and proteasomal degradation. Molecular glue degraders - monovalent small molecules that promote these neo-interactions - have emerged as powerful tools in this space. Serendipity was once synonymous with molecular glue discovery, but increasing mechanistic understanding is now guiding their rational design. In this review, we trace their evolution from chance discovery, explore the biological mechanisms that underpin molecular glue activity, examine key examples that have advanced into the clinic, and discuss the challenges that remain in harnessing these compounds for broader therapeutic impact.

Mitochondrial fatty acid oxidation (mFAO) disorders are caused by genetic variants in mFAO enzymes, their electron transporters, and cofactors. The clinical spectrum is heterogeneous, ranging from multi-organ failure and early death to milder neuromuscular forms that often are triggered or exacerbated during catabolic stress. Advances in genetics and the inclusion of mFAO disorders in newborn screening programs have allowed timely diagnosis and dietary interventions to prevent tissue damage and even death. Current dietary treatment aims to prevent energy deficiency and reduce toxic metabolites, but does not significantly prevent neurological, cardiac, and skeletal muscular abnormalities, including rhabdomyolysis. This review summarizes the present knowledge obtained from human studies showing that disruption of mitochondrial bioenergetics and redox homeostasis may represent relevant mechanisms for understanding long-term tissue damage and the stress-induced disease pathology of mFAO disorders. Sources and mechanisms of reactive oxygen species (ROS) production are discussed, including knowledge gained from mutations in the Electron Transfer Flavoprotein (ETF) and ETF-Ubiquinone Oxidoreductase (ETF-QO) proteins. The ETF/ETF-QO site serves as a biophysical and biochemical linker between mFAO and OXPHOS, and its high capacity for ROS production makes it a key component of the respiratory chain and a source of ROS in mFAO disorders. Understanding mitochondrial disturbances and how secondary disturbances in mFAO cofactors integrate with redox regulation at the ETF/ETF-QO site will advance our understanding of not only mFAO disorders but also the many diseases entailing OXPHOS and mFAO deficiencies, such as neurological and cardiovascular diseases, and as such, be enlightening for mitochondrial medicine in general.

Galectins, a family of sugar-binding proteins, play a multifaceted role in human health and disease. They do not only regulate cellular processes but also influence tumor development and progression by promoting tumor growth, angiogenesis, metastasis, and most importantly, immune evasion. Unraveling their role in oncology opens doors for innovative therapies and novel diagnostic tools. Intriguingly, another layer of control emerges with non-coding RNAs, microRNAs, long ncRNAs, and circular RNAs. These RNA molecules act as master regulators in cancer by targeting galectins. This interplay between galectins and non-coding RNAs presents a golden opportunity for targeted control of cancer hallmarks in which galectins are highly involved. Manipulating this interaction can potentially increase the effectiveness of existing cancer therapies, particularly immunotherapy. This exciting avenue holds immense promises for the development of novel and targeted cancer therapies. In this review, the authors explore the complex interplay between ncRNAs and galectin across various types of cancer.

Accurate and efficient DNA replication constitutes the most effective safeguard against genome instability. Numerous aspects of replication initiation, elongation, and termination are tightly regulated by post-translational modifications. In this review, we summarize recent advances in elucidating pathways regulated by ubiquitin and the small ubiquitin-like modifier, SUMO, and compare insights gained in yeast with those obtained in vertebrate systems. These reversible modifications play critical roles in both DNA replication and replication-coupled repair processes. When active replisomes encounter obstacles such as nucleotide depletion, DNA secondary structures, or base lesions that impede fork progression, multiple genome surveillance pathways are activated to coordinate the replication stress response. Stalled replication forks undergo remodeling and reversal, thereby stabilizing the fork and facilitating replication restart. In parallel, diverse tolerance mechanisms have evolved to enable lesion bypass or replication traverse, which transiently alters the replication machinery yet permits continuation of DNA synthesis. At the core of these processes are the DNA damage tolerance and Fanconi anemia pathways, whose components collaborate to prevent under-replication during S phase and beyond. Furthermore, ubiquitin and SUMO signaling act synergistically through the activity of SUMO-targeted ubiquitin ligases. These enzymes sequester damaged replication forks at the nuclear periphery and promote recombination-mediated restart under stringent spatiotemporal control of the replication checkpoint. Failure of these mechanisms forces the cell to engage in a final, "do-or-die" attempt to initiate DNA synthesis during mitosis, a process that is also orchestrated by ubiquitin signaling.

Triplex DNA structures form through the binding of a third oligonucleotide strand to the major groove of canonical double-stranded DNA at sites of extended polypurine sequence. Although they are known to be favored with certain sequence specificity and cellular conditions, including decreased pH and the presence of multivalent cations, there remains ambiguity in the structures and extent to which they form in vivo. Therefore, despite their biological relevance and many potential applications, the use of DNA triplexes in biotechnology has been limited to date. The focus of this review is to explore the intricacies of DNA triplex formation, as well as the current state of research into their functions and applications in molecular cell biology. The range of analytical, computational and synthetic chemistry techniques employed to investigate and enhance the stability of triplex assemblies is also reviewed. Understanding the structural properties that underpin triplex formation and activity, coupled with computational and synthetic methodologies to expand their utility, can unlock the potential of various triplex-forming oligonucleotides as a contemporary tool for regulating gene expression.

The aerobic respiratory chain is vital to bacterial and eukaryotic cell energy transformation. Embedded in the mitochondrial inner membrane and the bacterial plasma membrane, the respiratory chain couples sequential redox reactions with ion pumping, thereby generating the motive force that is used to drive ATP synthesis. Due to the essential role of oxidative phosphorylation in cellular life, the electron transport chain proteins, their cofactors, and ATP synthase components serve as a target for antibacterial, antifungal, and antiparasitic drugs. Whether by (1) inhibition of electron flow through transport chain complexes, (2) collapsing of the motive force, (3) competitive inhibition, or (4) blocking proton flow through the catalytic subunits of ATP synthase, small molecules can selectively inhibit bacterial, fungal, and parasitic life while not showing high toxicity in mammalian systems. Because of robust antimicrobial resistance against the traditional mechanisms of microbial control (cell wall integrity, protein synthesis, nucleotide and nucleic acid synthesis, etc.), the study of alternative targets, such as the respiratory chain, is prudent and timely. This review summarizes the current research on small molecule and peptide inhibition of the aerobic respiratory chain complexes, electron flow, and ion translocation in a series of human and plant pathogens.

Bacterial biofilms consist of bacterial communities embedded in a self-produced extracellular matrix (EM) known as the matrixome. The matrixome primarily comprises extracellular polymeric substances (EPS) and other elements. EPS encompassing exopolysaccharides, proteins, lipids, and nucleic acids plays a key role in maintaining structural integrity and is involved in various functions. Extracellular DNA (eDNA) released into the EM through various mechanisms, including cell lysis or autolysis, membrane vesicle-mediated release, phage-mediated release, active secretion, and Type VI secretion system (T6SS)-mediated eDNA release. Quorum sensing (QS), a vital signaling system during biofilm formation, also regulates the release of eDNA in a controlled manner by coordinating gene expression in response to cell density. Once released into the EM, eDNA interacts with EPS components, enhancing matrix stability, structural cohesion, and integrity. The present review comprehends the multifaceted roles of eDNA within the biofilm matrixome, highlighting its contribution to biofilm formation, stability, and functionality through various interactions and regulatory mechanisms. It also delves into the mechanisms of eDNA release and its interactions within the biofilm matrix. Understanding these complex roles of eDNA in regulating biofilm will provide insights into developing strategies to enhance the remediation of environmental pollutants and manage biofilm-associated problems in medical settings.