Biochemical Society transactions最新文献

Lipid droplets (LDs) originate from the endoplasmic reticulum (ER) and are unique among cellular organelles, as they consist of a hydrophobic core of neutral lipids that is surrounded by a phospholipid monolayer. Proteins and enzymes embedded into this monolayer are essential for regulating dynamic lipid storage and consumption and hence, for the cellular adaptation to metabolic changes. Their activity and abundance on the LD surface must therefore be well-controlled. Many of these proteins are first inserted into the phospholipid bilayer membrane of the ER before they partition to the LD monolayer. While a monotopic membrane topology is required for enabling the targeting of these ERTOLD proteins from the ER to LDs, the molecular mechanisms underlying this partitioning are only beginning to emerge. In this second part of the bipartite review 'Navigating lipid droplet proteins,' we discuss recent conceptual advances regarding ER-to-LD protein partitioning and focus on novel insights into the structural dynamics of LD-destined proteins, how their partitioning to LDs is temporally controlled, and the hierarchies involved in selective and competitive protein recruitment to LDs according to metabolic needs and functions.

The MET receptor tyrosine kinase is a pivotal regulator of cellular survival, motility, and proliferation. Mutations leading to skipping of exon 14 (METΔex14) within the juxtamembrane domain of MET impair receptor degradation and prolong oncogenic signaling, contributing significantly to tumor progression across multiple cancer types. METΔex14 mutations are associated with aggressive clinical behavior, therapeutic resistance, and poor outcomes. Next-generation sequencing from both tissue and liquid biopsies has significantly improved the detection frequency of METΔex14 in lung and other cancers. However, clinical trials targeting METΔex14 have rendered partial responses and mixed outcomes due to the lack of a comprehensive mechanistic understanding of METΔex14 regulation and a diverse mutational landscape. This review synthesizes current knowledge on the mechanistic basis of METΔex14-driven oncogenesis, including alterations in receptor dynamics, downstream signaling perturbations, genomic alterations underlying this mutation, and mechanisms of acquired therapeutic resistance. We further discuss the clinical implications of these insights and highlight future research directions essential for optimizing targeted therapies.

Lipid droplets (LDs) are cytosolic lipid storage organelles that derive from the endoplasmic reticulum (ER). Their biogenesis and function are essential for maintaining cellular lipid homeostasis and require a spatiotemporally co-ordinated recruitment of specific membrane proteins to the LD surface. Many LD-destined proteins are inserted into the ER phospholipid bilayer in a monotopic hairpin topology before they can partition to the LD monolayer. About a third of all cellular proteins enter the ER during their biogenesis, either as ER-resident or as secretory proteins. Decades of research have provided a solid understanding of which molecular machineries ensure ER targeting fidelity of transmembrane-spanning proteins. The molecular mechanisms underlying the biogenesis of LD-destined monotopic proteins, however, are only beginning to emerge. In this first part of the bipartite review 'Navigating lipid droplet proteins,' we provide an overview of the general principles underlying protein targeting to the ER. We highlight recent advances and current challenges regarding the specific mechanisms for LD-destined proteins and discuss their physiological implications. The molecular mechanisms underlying the subsequent ER-to-LD protein partitioning are at the heart of the second part of this bipartite review.

Acute leukemias are hematological malignancies characterized by the uncontrolled proliferation of immature bone marrow cells, disrupting normal hematopoiesis. These diseases, classified into acute lymphoblastic leukemia and acute myeloid leukemia (AML), often result from acquired genetic alterations that drive deregulated cell growth and inhibit differentiation. The cytoskeleton has emerged as a promising therapeutic target due to its pivotal role in cellular processes such as adhesion, motility, and division. Among its components, stathmin 1 (STMN1) and ezrin (EZR) stand out for their significant involvement in the pathogenesis and progression of acute leukemias. STMN1, a regulator of microtubule dynamics, is associated with chromosomal instability and leukemic cell proliferation, and is frequently overexpressed in these malignancies. Anti-microtubule agents, such as paclitaxel, eribulin, and cyclopenta[b]indole derivatives have demonstrated the ability to inhibit STMN1 by inducing its phosphorylation at regulatory sites, thereby impairing cell viability and promoting apoptosis. EZR, a membrane-actin linker protein, plays a critical role in cell signaling and tumor survival. Its overexpression has been correlated with poor prognosis in AML. Pharmacological inhibitors like NSC305787 have shown efficacy in reducing cell viability, modulating key pathways such as PI3K (phosphatidylinositol-3-kinase)/AKT (AKT serine-threonine protein)/mTOR (mammalian target of rapamycin), and enhancing the activity of standard chemotherapeutics, thereby supporting their potential use in combination therapies. This review aims to explore the roles of STMN1 and EZR in the pathogenesis of acute leukemias, assessing their potential as therapeutic targets. The goal is to synthesize recent evidence to guide the development of more effective inhibitors, focusing on overcoming therapeutic resistance and tailoring treatments to individual profiles.

The human genome attains an amazing spatial organization in the packaging of 2 m of DNA into a 10-μm nucleus. Such structural organization is achieved by the folding of chromatin and the regulation exerted by architectural proteins such as insulators. Chromatin insulators are boundary elements of the genome that, through enhancing blocking activities, demarcation of chromatin domains, and chromatin looping, regulate transcription. The review focuses on the identification and characterization of insulators in various species, discussing mainly the functions of the CCCTC-binding factor (CTCF) in mammals and functionally equivalent insulator proteins in Drosophila melanogaster. We review here the mechanisms of enhancer blocking, barrier activity, and loop extrusion, emphasizing their effects on topologically associating domains and chromatin architecture. Furthermore, we discuss new concepts that have come into prominence: tethering elements and redundancy among the insulator proteins, which contribute to chromatin organization. Advances in methodology, including chromosome conformation capture and high-resolution imaging techniques, have transformed our view of the dynamic interplay between the architecture of chromatin and transcription regulation. This review discusses the importance of insulators for genome organization and describes future directions in investigating their roles in both gene regulation and three-dimensional genomic architecture.

The discovery of immune checkpoint blockade as a therapeutic strategy to induce immunogenic cancer cell elimination has shown great success in the treatment of various cancers. However, limited response rates highlight the need for further development in this field. Promising new preclinical developments include the discoveries of proteolysis-targeting chimeras (PROTACs) to interfere with tumor immune escape signaling. Pharmacological induction of targeted protein degradation by these chimeras has shown advantages in inhibiting non-enzymatic protein functions and difficult to target protein-protein interactions. Furthermore, the induced degradation was shown to promote changes in the major histocompatibility complex I ligandome, which can be leveraged for an immune stimulus, increasing the cancer immune response. In this minireview, we highlight the research efforts ongoing towards employing PROTACs in immunotherapy for cancer treatment. Specifically, we outline how the unique mechanism of action can be leveraged to enhance the immune response or inhibit immune suppression.

Plants use light as an energy source to reduce carbon dioxide into carbohydrates during photosynthesis. However, when the incident light exceeds the photosynthesis rate, the excess energy must be dispersed, or it can result in the unregulated formation of harmful reactive oxygen species, especially in plants exposed to very high light or abiotic stress conditions that compromise photosynthetic efficiency. The excess energy is typically dispersed harmlessly as heat, which can be measured as non-photochemical quenching (NPQ) of chlorophyll fluorescence. NPQ kinetics vary within plant populations, and understanding the basis of this variation will contribute to improving resiliency to abiotic stresses, including high light, in crops. Here it is reviewed how three key NPQ genes, Photosystem II subunit S (PsbS), Violaxanthin de-epoxidase (VDE), and Zeaxanthin epoxidase (ZEP), contribute to natural variation in NPQ kinetics. PsbS expression level is an important determinant of NPQ variation, whereas VDE and ZEP contribute to NPQ variation via post-translational regulation related to natural variation in many genes affecting these enzymes' activity. Post-translational mechanisms that influence NPQ, including redox regulation via thioredoxins and regulation of ascorbate availability, thylakoid lumen pH, and violaxanthin accessibility are discussed. There are also addressed NPQ regulatory mechanisms beyond PsbS, ZEP, and VDE, including natural regulation of light accessibility, modulation of light harvesting, and feedback from the steps following light harvesting. Finally, how this knowledge can be harnessed to engineer more resilient crops is briefly summarized.

Most sexually reproducing eukaryotes use a specialized cell division called meiosis to halve the complement of chromosomes in their gametes. During meiotic prophase I, homologous chromosomes (homologs) recombine by reciprocally exchanging DNA to form cross-overs (COs) that are required for accurate chromosome segregation. COs also reshuffle parental genomes to create genetic diversity among progeny. Molecular genetic studies have identified hundreds of genes involved in meiotic recombination, which have been well summarized in several reviews. Here, we highlight recent advances in understanding endogenous mechanisms that regulate the frequency and distribution of meiotic COs, also called CO patterning. Specifically, we focus on genome-wide regulation, epigenetic control, transcription regulation, and post-transcription processes. Additionally, we highlight open questions that still need further investigation in this field.

In myriad arthropod species, maternally transmitted symbiotic bacteria spread through populations by manipulating host reproduction, most frequently by a mechanism called cytoplasmic incompatibility (CI). CI occurs when bacterially infected males fertilize uninfected females, typically causing paternal chromatin condensation and segregation defects and usually embryonic arrest in the first zygotic cell cycle. Embryos survive if the female is similarly infected, which promotes bacterial spread. The endosymbiont best known for CI is Wolbachia, now widely used against mosquitoes that vector viral diseases such as dengue fever. Although CI is induced by Wolbachia resident in testes, mature sperm carry no bacteria, indicating they alter sperm in a way that, following fertilization, interferes with embryogenesis. CI-inducing factors (Cifs) are expressed from syntenic Wolbachia cifA-cifB genes. CifB is required in the male germline to induce CI, while CifA expression in the host female is sufficient to rescue viability. Importantly, CifA suppresses lethality through its binding to CifB. Different CifB proteins have distinct CI-relevant enzymatic functions, in particular, deubiquitylase and nuclease activities. Consistent with these genetic data, CifB is packaged into sperm during spermiogenesis. While sperm morphological disruption has been observed in fruit flies carrying cif transgenes, a causal role in CI is unclear. Also not understood is how maternally provisioned CifA rescues embryo viability. Exciting new findings with diverse symbiotic bacteria reveal cifA-cifB-like operons on extrachromosomal plasmids. These results suggest far wider deployment of Wolbachia-related CI factors than previously thought and multiple mechanisms for lateral cif gene transfer.