The FEBS journal最新文献

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Despite extensive research, the mechanistic underpinnings driving CRC progression remain largely unknown. As a fundamental component of the brush border cytoskeleton, villin-1 (VIL1) acts as a marker for intestinal cell differentiation and maturation. Through a comprehensive transcriptomics analysis of eight studies (total sample: n = 1952), we consistently observed significant upregulation of VIL1 expression in CRC tumors compared with adjacent normal tissue. In our independent cohort, this notable upregulation has been further validated at both mRNA and protein levels in colon tumor tissues, relative not only to adjacent normal tissue but also to normal controls. Our data show that VIL1 promotes proliferation and migration while inhibiting apoptosis. Conversely, knockout of VIL1 suppresses proliferation and migration while inducing apoptosis. Mechanistically, we reveal that knocking out VIL1 activates ferroptosis and inhibits the migration of CRC cells, while overexpressing VIL1 yields the opposite effects, and vice versa. Additionally, VIL1 binds to Nuclear factor NF-kappa-B p105 subunit (NF-κB) and controls NF-κB expression. In vivo, overexpressing VIL1 inhibits ferroptosis, and induces the expression of NF-κB and lipocalin 2 (LCN2), thereby promoting CRC tumor growth. Thus, we have identified the VIL1/NF-κB axis as a pivotal regulator of CRC progression through ferroptosis modulation, unveiling VIL1 as a promising therapeutic target for CRC treatment via ferroptosis. Our study offers novel avenues for exploring the therapeutic potential of ferroptosis in CRC management, emphasizing the high potential of VIL1 in regulating colorectal tumorigenesis.

This editorial highlights and celebrates the winner of the 2024 Richard Perham prize. This was selected from shortlisted original articles that were published in The FEBS Journal in 2023 and received prize nominations from the Editorial Board. The winning paper, by Matteo Brindisi, Luca Frattaruolo, Federica Sotgia, Michael P Lisanti, Anna Rita Cappello and colleagues, shows how high cholesterol levels promote breast cancer aggressiveness.

This review consolidates a decade of research on fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1), a mitochondrial oxaloacetate tautomerase and decarboxylase with profound implications in cellular metabolism. Despite its critical role as a regulator in mitochondrial metabolism, FAHD1 has remained an often-overlooked enzyme in broader discussions of mitochondrial function. After more than 12 years of research, it is increasingly clear that FAHD1's contributions to cellular metabolism, oxidative stress regulation, and disease processes such as cancer and aging warrant recognition in both textbooks and comprehensive reviews. The review delves into the broader implications of FAHD1 in mitochondrial function, emphasizing its roles in mitigating reactive oxygen species (ROS) levels and regulating complex II activity, particularly in cancer cells. This enzyme's significance is further highlighted in the context of aging, where FAHD1's activity has been shown to influence cellular senescence, mitochondrial quality control, and the aging process. Moreover, FAHD1's involvement in glutamine metabolism and its impact on cancer cell proliferation, particularly in aggressive breast cancer subtypes, underscores its potential as a therapeutic target. In addition to providing a comprehensive account of FAHD1's biochemical properties and structural insights, the review integrates emerging hypotheses regarding its role in metabolic reprogramming, immune regulation, and mitochondrial dynamics. By establishing a detailed understanding of FAHD1's physiological roles and therapeutic potential, this work advocates for FAHD1's recognition in foundational texts and resources, marking a pivotal step in its integration into mainstream metabolic research and clinical applications in treating metabolic disorders, cancer, and age-related diseases.

Alexander Wlodawer is a structural biologist who has made seminal contributions to our understanding of protein structure-function relationships. He obtained his PhD from the University of California, Los Angeles, and has spent the majority of his career at the National Cancer Institute in Frederick, Maryland, where he currently holds a Senior Investigator position at the NCI's Center for Structural Biology. He has been a member of the Editorial Board of The FEBS Journal since 2007. In this interview, Alex talks about carving his own scientific path, the era of 'big things' in structural biology, and the most challenging editorial task.

Carbonic anhydrases (CAs) are ideal catalysts for carbon dioxide sequestration in efforts to alleviate climate change. Here, we report the characterisation of three α-CAs that originate from the thermophilic bacteria Persephonella hydrogeniphila (PhyCA), Persephonella atlantica (PaCA), and Persephonella sp. KM09-Lau-8 (PlauCA) isolated from hydrothermal vents. The three α-Cas, showing high sequence similarities, were produced in Escherichia coli, purified and characterised. Surprisingly, they revealed very different behaviours with regards to their thermostability profiles. PhyCA presented a more stable thermostability profile amongst the three, thus we chose it for rational engineering to improve it further. PhyCA's residue K88, a proton transfer residue in α-CAs, was mutated to His, Ala, Gln and Tyr. A 4-fold activity improvement was noted for variants K88H and K88Q at 30 °C, owing to the higher proton transfer efficiency of the replacement proton transfer residues. K88Q also proved more stable than PhyCA. K88Y did not increase activity, but notably increased thermal stability, with this enzyme variant retaining 50% of its initial activity after incubation for 1 h at 90 °C. Removal of the two main proton shuttles (variant H85A_K88A) resulted in diminished activity of the enzyme. Molecular dynamics simulations performed for PhyCA and all its variants revealed differences in residue fluctuations, with K88A resulting in a general reduction in root mean square fluctuation (RMSF) of active site residues as well as most of the CA's residues. Its specific activity and stability in turn increased compared to the wild type.

The enzyme glucose-1-phosphate adenylyltransferase (GlgC, EC:2.7.7.27) catalyses the first step in glycogen synthesis by converting glucose-1-phosphate into ADP-glucose, which is added in turn to a growing glycogen chain by glycogen synthases. Thus far, in vitro studies of GlgC were mainly performed using colorimetric or radiolabel-based phosphate release assays, limiting the option for analysing this reaction. With this work, we present a novel in vitro continuous assay coupling the subsequent glycogen synthase reaction to the GlgC reaction, thus simulating the process of glycogen synthesis in vivo. Using this assay, we revisited GlgC catalytic parameters and screened for metabolites that affect GlgC activity in Synechocystis sp. PCC 6803. We also describe in further detail the antagonistic interplay between the GlgC activator, 3-PGA and the inhibitor, inorganic phosphate, revealing the intricate mechanism by which glycogen formation responds to fluctuations in carbon and energy supply in cyanobacteria.

Chimeric antigen receptor T (CAR-T) cell therapy, which targets CD19 for hematological malignancies, represents a breakthrough in cancer immunotherapy. However, some patients may develop resistance to CAR-T treatment, underscoring the importance of optimizing CAR-T design to enhance responsiveness. Here, we investigated the impact of different subpopulations in anti-CD19 CAR-T cells on the tumoricidal effect. Different populations of anti-CD19 CAR-T cells were isolated by magnetic-activated cell sorting (MACS). Their lytic activities on the acute lymphocytic leukemia cell line SUP-B15 and diffuse large B-cell lymphoma EB-3 cell line were examined in a co-culture system. The anti-tumorigenic outcome of different CAR-T cell compositions was evaluated in a xenograft mouse model of EB-3 cells. CD8⁺CAR-T cells exhibited the most potent tumoricidal activity against SUP-B15 and EB-3 cells. Additionally, CD4⁺ T helper cells enhanced the lytic effects of CD8⁺ CAR-T cells by increasing the availability of interleukin-2 (IL-2). Depleting CD25⁺Treg (T regulatory) cells from CD4⁺CAR-T population further augmented the tumoricidal activity of CD8⁺CAR-T cells by preventing IL-2 deprivation. Consistently, in vivo experiments demonstrated that the CD4⁺CD25⁺ Treg population dampened the antitumor activity of CD8⁺CAR-T cells, while depletion of Tregs from CD4⁺CAR-T cells enhanced the tumoricidal effect. These findings emphasize the potential role of CAR Treg cells in therapeutic resistance, suggesting that the depletion of Tregs in the anti-CD19 CAR-T population may serve as a strategy to augment the anticancer effect of CD8⁺CAR-T cells.

Distinct and seemingly independent cellular pathways affecting intracellular machinery or extracellular matrix (ECM) deposition and organization have been implicated in aneurysm formation. One of the key genes associated with this pathology in both humans and mice is lysyl oxidase (LOX), a secreted ECM-modifying enzyme, highly expressed in medial vascular smooth muscle cells. To dissect the mechanisms leading to aneurysm development, we conditionally deleted Lox in smooth muscle cells. We find that cytoskeletal organization is lost following Lox deletion. Cell culture assays and in vivo analyses demonstrate a cell-autonomous role for LOX affecting myosin light-chain phosphorylation and cytoskeletal assembly resulting in irregular smooth muscle contraction. These results not only highlight new intracellular roles for LOX, but notably, they provide a link between multiple processes leading to aneurysm formation, suggesting LOX coordinates ECM development, cytoskeletal organization, and cell contraction required for media development and function.

Oxidative stress is a key component of many diseases, including neurodegenerative diseases such as Alzheimer's disease. Reactive oxygen species (ROS) such as hydrogen peroxide and nitric oxide lead to disease progression by binding to proteins and causing their dysregulation. Metallothionein-3 (MT3), a cysteine-rich brain-located metalloprotein, has been proposed to be a key player in controlling oxidative stress in the central nervous system. We report data from a combination of electrospray ionization mass spectrometry (ESI-MS), ultraviolet (UV)-visible absorption spectroscopy, and circular dichroism spectroscopy that identify the oxidation pathway of MT3 fully bound to endogenous Zn(II) or exogenous Cd(II) together with the partially metalated species. We characterize the intermediate species formed during the oxidation of MT3, which is dominated by disulfide bond formation. We report the rates of oxidation. For both fully and partially metalated MT3, MT3 is oxidized at 5 to 10 times the rate of MT1, a similar but kidney-expressed isoform of MT. As oxidation progresses, MT3 follows a domain-specific demetallation pathway when it is fully metalated, and a domain-independent pathway when partially metalated. This suggests the presence of a significant susceptibility toward oxidation when MT3 is partially metalated, and, therefore, a possible protective role of Zn(II) when fully metalated. With the evidence for the rapid oxidation rate, our data support the proposals of MT3 as a key antioxidant in physiology.

In animals, adaptive transcription is a crucial mechanism to connect environmental stimulation to changes in gene expression and subsequent organism remodeling. Adaptive transcriptional programs involving molecules such as CREB, SRF, MEF2, FOS, and EGR1 are central to a wide variety of organism functions, including learning and memory, immune system plasticity, and muscle hypertrophy, and their activation increases cellular resilience and prevents various diseases. Yet, they also form the basis for many maladaptive processes and are involved in the progression of addiction, depression, cancer, cardiovascular disorders, autoimmune conditions, and metabolic dysfunction among others and are thus prime examples for mediating the adaptation-maladaptation dilemma. They are implicated in the therapeutic effects of major treatment modalities such as antidepressants and can have negative effects on treatment, for example, contributing to therapy resistance in cancer. This review examines the universal role of adaptive transcription as a mechanism for the induction of adaptive cell state transitions in health and disease and explores how many medical disorders can be conceptualized as caused by errors in cellular adaptation goals. It also considers the underlying principles in the basic structure of adaptive gene programs such as their division into a core and a directional program. Finally, it analyses how one might best reprogram cells via targeting of adaptive transcription in combination with complex stimulation patterns to leverage endogenous cellular reprogramming dynamics and achieve optimal health of the whole organism.