FEBS Letters最新文献

MiRNA export is a tightly regulated process crucial for maintaining balanced miRNA and target gene expression levels in metazoan cells. RNA-interacting proteins such as HuR play a key role in the selectivity and specificity of miRNA export, thereby enabling context-dependent release of gene-repressing miRNAs from mammalian cells. Our results demonstrate that activated macrophages cooperatively export miRNAs, where hepatic miR-122 significantly enhances the export of miR-146a and other miRNAs. We also observe that this cooperative export causes a synchronized increase in the expression of pro-inflammatory target genes in activated macrophages. In investigating the molecular mechanisms, we found that the miRNA-binding protein HuR cooperatively binds to miRNAs and promotes their entry into endosomes, thereby facilitating their cooperative export. This highlights the selective and cooperative nature of endosome targeting happening in activated macrophages as a prerequisite for extracellular vesicle-mediated miRNA export. Impact statement This study uncovers a new mechanism for miRNA export regulation in mammalian cells, driven by the RNA-binding protein HuR. In macrophages, HuR cooperatively binds with miRNAs to export both low- and high-affinity substrates, thereby influencing macrophage activation. This cooperative export method is a common strategy for coordinated miRNA release across different cells.

The ESX-5 secretion system in Mycobacterium tuberculosis exports PE/PPE virulence factors, with EccA5, an AAA+ ATPase, playing a pivotal role. We solved the crystal structure of EccA5's N-terminal TPR domain (EccA5NT) at 2.15 Å, revealing a monomeric fold with six TPR motifs and a variable β-finger. Biophysical studies, including SAXS and size exclusion chromatography, confirm its monomeric state. A flexible loop (residues 137-148) suggests dynamic substrate interactions. SPR, SAXS and in silico docking show moderate binding (K_D = 3.43 μm) between EccA5NT's β-finger and EspG5's β2-β3 loop, indicating a role in PE/PPE-EspG5 complex disassembly. These findings elucidate the role of EccA5 in ESX-5-mediated secretion.

Adrenergic-driven thermogenic activation of brown adipose tissue requires high amounts of nutrients including iron to support mitochondrial biogenesis. This is governed by rapid gene expression changes in ex vivo differentiated human cervical-derived brown adipocytes. Transferrin receptor 1 (TFRC) is upregulated in response to dibutyryl-cAMP. We aim to investigate the mechanism of facilitated iron uptake when thermogenesis is activated. Pharmacological inhibition and siRNA-mediated knock-down of TFRC during stimulation decrease intracellular iron content and prevent elevation of oxygen consumption and induction of thermogenic markers. Deferoxamine-mediated iron chelation also shows comparable effects. Contrarily, the expression of ferroportin exporter is suppressed during activation; however, its inhibition does not increase thermogenesis. Brown adipocytes constitutively express and secrete high amounts of transferrin, while melanotransferrin expression and release are upregulated only in activated adipocytes. In silico analysis suggests that melanotransferrin interacts with the helical domain of TFRC. Our findings support that iron is critical in stimulating adipocyte thermogenesis.

Centrosome abnormalities can lead to erroneous chromosome segregation during cell division, resulting in genomic instability. We identified a cancer-associated heterozygous missense mutation (S76L) in the centrosome protein STIL that promotes centrosome amplification and DNA damage. STIL was found to interact with BRCA1 regulating its stability; this, however, is disrupted by the S76L mutation. Mimicking the heterozygous state by overexpressing STIL-S76L redistributed BRCA1 from the nucleus to centrosomes and elevated centrosomal Aurora-A and PLK1 kinases that are responsible for centrosome amplification. Decreased nuclear BRCA1 in the mutant state induced DNA damage, which was rescued by co-expression of wild-type but not nuclear localization-deficient BRCA1. Despite amplified centrosomes, mutant cells maintain pseudo-bipolar spindle organization via kinesin HSET (KIFC1)-dependent clustering, a known cancer survival mechanism and potential therapeutic target. Together, our findings uncover a previously unrecognized STIL-BRCA1 regulatory axis that safeguards centrosome homeostasis and genome integrity. Impact statement Our study reveals a cancer-associated STIL mutation that disrupts its interaction with BRCA1, thereby destabilizing BRCA1 and leading to centrosome amplification and DNA damage.

Myeloid-derived suppressor cells (MDSCs) differentiate and proliferate in the pathological context of cancer, suppress T-cell responses, and promote tumor progression and therapeutic resistance. These cells express high levels of TNF receptor type 2 (TNFR2), but the ligand TNF-α also activates TNFR1, masking TNFR2-specific function. We analyzed TNFR2 signaling using GM-CSF-induced MDSCs from TNFR2-knockout mice and scR2agoTNF-Fc, a TNFR2-selective agonist. Stimulation with scR2agoTNF-Fc maintained a highly suppressive monocytic subset. TNFR2 deficiency reduced MDSC-mediated T-cell suppression. TNFR2 activation also increased the expression of immunosuppressive effector molecules such as inducible nitric-oxide synthase and interleukin-10. These results indicate that TNFR2 is a promising therapeutic target for modulating the differentiation and immunosuppressive functions of MDSC subsets.

Abnormal accumulation of misfolded proteins is a hallmark of neurodegenerative diseases. Amyloid aggregation of α-synuclein (α-Syn) and TAR DNA-binding protein 43 (TDP-43) contributes to Parkinson's disease and frontotemporal dementia, respectively. The heterotypic aggregates are increasingly recognized as highly cytotoxic. Given the frequent co-occurrence of α-Syn, TDP-43, and tau pathologies, we examined whether the first prion-like domain (PRD1) of CPEB3 modulates α-Syn and TDP-43 aggregation. Nuclear magnetic resonance (NMR) relaxation experiments revealed a direct interaction between PRD1 and the amyloid core of α-Syn, suppressing its aggregation, while phase separation assays showed delayed liquid-liquid phase separation (LLPS) -mediated α-Syn aggregation. In contrast, no interaction was detected with the C-terminal domain of TDP-43 (TDP-43_CTD), indicating selective inhibition of α-Syn aggregation by PRD1.

Liver cancer stands as the sixth leading cause of cancer-related deaths globally, with hepatocellular carcinoma (HCC) being the most frequently diagnosed subtype. The hepatic tumor microenvironment (TME) comprises a complex array of cellular and non-cellular components, including activated hepatic stellate cells (HSCs), tumor-associated macrophages (TAM), endothelial cells, immune cells, and non-cellular elements such as growth factors, proteolytic enzymes, inhibitors, and extracellular matrix (ECM) proteins. The initiation and progression of HCC involve intricate interactions among hepatocytes, tumor cells, and non-tumor cells, including liver-resident non-parenchymal cells (NPCs). The Hippo-YAP pathway plays a crucial role in tumor development and initiation. YAP/TAZ, as primary effectors of the Hippo pathway, intricately connect with other signaling pathways relevant to tumors. YAP promotes the growth of cancer stem cells, the development of malignant phenotypes, and drug resistance, contributing significantly to cancer growth. This review focuses on the role of YAP in stromal cells as a mediator of HCC. We aim to present a comprehensive overview, not only consolidating existing knowledge but also paving the way for innovative exploration in pursuing effective therapeutic strategies against HCC.

Large-scale perturbational approaches have transformed cancer research, enabling systematic identification of tumour-specific dependencies and therapeutic vulnerabilities. However, many clinically relevant vulnerabilities arise from genetic interactions, including synthetic lethal and buffering relationships, and are shaped by cellular state, lineage and treatment history. Interpreting complex dependency landscapes increasingly relies on advanced computational and AI-based approaches integrating molecular, phenotypic and contextual information. In this rapidly evolving setting, dedicated forums are needed to connect experimental and computational perspectives. Following the success of the inaugural European Cancer Dependency Map Symposium, the 2nd EuroDepMap was held on 20 November 2025 at Human Technopole in Milan, bringing together leading scientists in functional genomics, genome-editing screens, disease models and AI-driven analysis, marking a pivotal moment for the field.

The substantial increase in food allergy prevalence during the last decades has made it a significant public health concern, affecting around 10% of the global population, especially children. Despite significant progress in understanding the general mechanisms of allergic sensitization, the development of oral tolerance remains a major challenge in advancing food allergy research and treatment. Additionally, each allergenic food source has a distinct immunological profile and tolerance trajectory, further complicating research efforts. Currently, oral allergen-specific immunotherapy is the only treatment that can help build tolerance to certain food allergens over time-although treatment outcomes vary. While B cells have been described and studied for their pathogenic role in food allergy, recent evidence suggests that they also modulate allergic responses through various effector and humoral functions. Notably, despite their low frequency, recent knowledge on the molecular and functional characteristics of food allergen-specific memory B cells has revealed important functions during both disease progression and therapeutic intervention. This review summarizes the current knowledge of IgE-mediated food allergy, highlighting the role of B cells, especially allergen-specific ones, in both disease and immune tolerance.

Aggregated amyloid beta peptide (Aβ) contributes to Alzheimer's disease through neurotoxic effects and a prion-like mode of transmission. We report that protein disulfide isomerase (PDI) exhibits disaggregase activity against oligomeric but not fibrillar forms of Aβ. PDI did not bind monomeric Aβ, indicating its highly effective inhibition of fibril formation occurs through reversal of early-stage oligomers rather than prevention of the initial aggregate. Cells exposed to both PDI and oligomeric Aβ were protected from Aβ-induced toxicity. An S-nitrosylated form of PDI that is associated with neurodegeneration could not bind to oligomeric Aβ, thereby eliminating its neuroprotective disaggregase activity. Our observations suggest PDI could be used both physiologically and therapeutically to dissolve the oligomeric forms of Aβ.