FEBS Letters最新文献

Phosphoinositides, comprising less than 10% of membrane lipids, function as 'lipid codes' within cellular compartments through seven species formed by myo-inositol headgroup phosphorylation. This review examines their diverse roles in endocytic transport, encompassing endocytosis, endosomal sorting, degradation, and recycling, as well as specialized mechanisms, such as caveolin-mediated endocytosis. The review also investigates the involvement of specific kinases and phosphatases in these processes. Additionally, it discusses the impact of technological advancements, such as fluorescent biosensors, super-resolution microscopy, optogenetics, and synthetic biology, on elucidating phosphoinositide dynamics during endocytic trafficking. Perturbations in phosphoinositide metabolism have been associated with human diseases, including cancer and neurodegenerative disorders. Exploring these pathways may unveil potential therapeutic targets, with subsequent research focusing on their spatiotemporal regulation, tissue-specific metabolism, the synergistic effects of phosphoinositides with other lipids, and the incorporation of systems biology to bridge basic cell biology with translational medicine.

Inositol phosphates (InsPs) represent a conserved class of water-soluble signaling molecules found in all eukaryotes. Their biosynthesis involves a tightly regulated enzymatic network, with inositol polyphosphate multikinase (IPMK) functioning as a pivotal catalytic hub. IPMK exhibits broad substrate specificity, phosphorylating various InsPs and phosphatidylinositol 4,5-bisphosphate. Beyond its enzymatic activity, IPMK also modulates key signaling pathways through noncatalytic mechanisms, including direct interactions with protein partners. This review highlights the functional attributes of IPMK, its diverse roles in cellular physiology and disease, and outlines current challenges and future directions in IPMK research.

Transglutaminase 2 (TG2) exhibits various protein-modifying catalytic and protein-protein interaction properties and is highly expressed in endothelial cells. To provide insight into its endothelial functions, the TG2 interactome was identified in HUVECs using biotinylated recombinant TG2 and affinity chromatography. Subsequently, endogenous TG2-silenced and a triple Flag-tagged transgenic TG2-expressing HUVEC line was created, allowing isolation of intracellularly assembled TG2-interacting proteins. Conformation-dependency of TG2's interactome was also determined. RNA-binding proteins associated with TG2 were the most enriched gene ontology terms in all experiments, with a 42% overlap between the TG2 interactome and known RNA-binding proteins in HUVECs. Consistent with TG2's recently described RNA-binding ability, our findings reveal its potential role in post-transcriptional regulation at a central hub within the RNA-binding protein network.

In eukaryotes, nuclear size scales with cell size, maintaining a constant nucleocytoplasmic volume ratio, known as the N/C ratio. Although nucleocytoplasmic transport plays a crucial role in nuclear size control, the underlying mechanisms remain elusive. Here, we investigated the impact of overexpression of a nuclear export signal (NES) fused with GFP (NES-GFP) in fission yeast on nuclear size. The overexpression of NES-GFP disrupts nuclear export, leading to the nuclear accumulation of cargo proteins and the formation of intranuclear microtubule bundles, thereby increasing the nuclear volume to cell volume (N/C) ratio dependent on nuclear import and microtubule nucleation. Enhanced formation of intranuclear microtubule bundles in cells overexpressing NES-GFP further accelerates nuclear expansion. We propose that membrane tension in the nucleus plays an important role in nuclear size control.

Elevated levels of extrachromosomal DNAs (ecDNAs) are associated with poor prognoses of many cancer types. These large circular DNAs typically harbour oncogenes and regulatory elements which, together with high levels of ecDNA transcription, confer a growth advantage to cancer cells. Replication of ecDNAs, followed by their unequal distribution at mitosis, further promotes rapid cancer evolution. In contrast to ecDNAs, the role of circular DNA by-products from V(D)J recombination in cancer development has largely been overlooked. Developing lymphocytes generate millions of excised signal circles (ESCs) each day through gene rearrangement at the immunoglobulin and T-cell receptor loci. Despite their similar size to ecDNAs, ESCs were long assumed to be inert and lost during cell division. However, it is now known that ESCs potently trigger genome instability when complexed with recombinase proteins. Not only this, but new data show that just like ecDNAs, ESCs replicate and persist, with high levels strongly correlating with poor prognosis of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Despite these striking similarities, the properties of ESCs and ecDNAs are seldom linked. Here, we provide the first comparative review of ecDNAs and ESCs, and highlight the reasons why these molecules are more closely related than once assumed.

The maintenance of protein homeostasis is a fundamental premise for the survival of all life. The synthesis, folding, localization, and degradation of thousands of proteins must be organized according to various conditions. To ensure such a stable and functional proteome, the proteostasis network evolved. Dedicated to this, the fourth School on Proteostasis, a co-funded EMBO|FEBS Lecture Course in memory of Susan Lindquist, took place in Espoo, Finland on 16–19 September 2025, with 59 early career researchers (PhD students or postdoctoral fellows), 18 leading scientists, and two editors attending and discussing the current state of the field. From basic principles to the latest therapeutic developments, this meeting provided a comprehensive overview of proteostasis. This report summarizes the lecture course and highlights selected presentations.

Parenthood has been linked to lower retention of women in academia, yet the specific challenges faced by mothers remain underexplored. We interviewed nine mothers across different career stages in the life sciences to qualitatively examine how motherhood intersects with academic milestones. Participants described challenges unique to academia, including dependence on supervisors, publication pressure, financial strain, and limited awareness of available institutional resources. They also shared strategies that supported their success, such as transparent communication with supervisors, designating student–parent coordinators, and creating peer communities for mothers in academia. By highlighting shared barriers and effective solutions, this work underscores the need for structural and cultural reforms to better support mothers in academia and retain talented scientists in STEM fields.

Almost all organisms on earth undergo rhythmic physiological and behavioral changes over the course of day. These rhythms are fundamental in most organisms and are referred to as circadian rhythms. The molecular mechanisms regulating these changes have evolved significantly in different kingdoms of life and they engage in crosstalk with most cellular functions. These molecular mechanisms have been studied for a long time using different model organisms and carefully designed experiments. In the past two decades or so, with advances in high throughput technologies and access to ever increasing computational power, the molecular mechanisms regulating circadian rhythms are being explored at multiple spatial and temporal scales. In this review, we introduce diverse regulatory mechanisms of circadian rhythms. We then focus on the proteins involved in circadian regulation, their structures, complexes and dynamics. This is followed by a review of computational methods such as structural modeling, integrative modeling and molecular simulations as applied to understanding the clock proteins in different organisms and insights obtained from the same. Finally, we highlight the limitations and future prospects of these methods in understanding the circadian regulation.

ETS family transcription factors can mediate mutant p53 functions, but there has been no comprehensive analysis of p53 interaction across the ETS family. By comparing direct mutant p53 binding between 26 ETS proteins, we found that all bound mutant p53, but relative binding differed significantly. The ETS DNA binding domain provided a common interaction interface, but strong binding required an alternate interaction domain highlighted by a PXXPP motif found in five ETS proteins. Genome-wide mapping found that the ETS protein ERG mediated some mutant p53 DNA binding in prostate cancer cells. Lastly, ETS proteins that interact strongly with mutant p53 tended to be upregulated in p53 mutant ovarian cancer. These results identify multiple ETS family members that could mediate mutant p53 function in cancer. Impact statement The mechanisms behind gain-of-function mutant p53 remain unclear. Here we identify distinct domains and a novel motif that can mediate binding of mutant p53 to multiple different ETS family transcription factors.

During gene expression, ribosome stalling frequently occurs and can lead to detrimental effects on cellular homeostasis. Several quality control mechanisms, including ribosome-associated quality control (RQC) and nonfunctional ribosomal RNA decay (NRD), have been identified to resolve these aberrant translation events. While the molecular mechanisms of each pathway have been extensively characterized, the mechanisms underlying the mutual regulation of the expression of pathway factors remain to be elucidated. Here, we employed a series of knockout mouse and human cell lines to investigate the crosstalk between translational quality control factors. Our findings revealed that the E3 ubiquitin ligase LTN1 suppresses expression of the E3 ubiquitin ligase RNF10 in a manner dependent on the RING domain of LTN1. This discovery offers new insights into the coordination of translational surveillance pathways.