The FEBS journal最新文献

Maintaining cellular homeostasis in the face of stress conditions is vital for the overall well-being of an organism. Reactive oxygen species (ROS) are among the most potent cellular stressors and can disrupt the internal redox balance, giving rise to oxidative stress. Elevated levels of ROS can severely affect biomolecules and have been associated with a range of pathophysiological conditions. In response to oxidative stress, yeast activator protein-1 (Yap1p) undergoes post-translation modification that results in its nuclear accumulation. YAP1 has a key role in oxidative detoxification by promoting transcription of numerous antioxidant genes. In this study, we identified previously undescribed functions for NCE102, CDA2, and BCS1 in YAP1 expression in response to oxidative stress induced by hydrogen peroxide (H₂O₂). Deletion mutant strains for these candidates demonstrated increased sensitivity to H₂O₂. Our follow-up investigation linked the activity of these genes to YAP1 expression at the level of translation. Under oxidative stress, global cap-dependent translation is inhibited, prompting stress-responsive genes like YAP1 to employ alternative modes of translation. We provide evidence that NCE102, CDA2, and BCS1 contribute to cap-independent translation of YAP1 under oxidative stress.

Antigen-specific B and T cell responses play a critical role in vaccine-mediated protection against infectious diseases, but these responses are highly variable between individuals and vaccine immunogenicity is frequently sub-optimal in infants, the elderly and in people living in low- and middle-income countries. Although many factors such as nutrition, age, sex, genetics, environmental exposures, and infections may all contribute to variable vaccine immunogenicity, mounting evidence indicates that the gut microbiota is an important and targetable factor shaping optimal immune responses to vaccination. In this review, we discuss evidence from human, preclinical and experimental studies supporting a role for a healthy gut microbiota in mediating optimal vaccine immunogenicity, including the immunogenicity of COVID-19 vaccines. Furthermore, we provide an overview of the potential mechanisms through which this could occur and discuss strategies that could be used to target the microbiota to boost vaccine immunogenicity where it is currently sub-optimal.

DABMA is a chemical molecule optimized from the parent compound ABMA and exhibits broad-spectrum antipathogenic activity by modulating the host's endolysosomal and autophagic pathways. Both DABMA and ABMA inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a cellular assay, which further expands their anti-pathogen spectrum in vitro. However, their precise mechanism of action has not yet been resolved. TMEM175 is a newly characterized endolysosomal channel which plays an essential role in the homeostasis of endosomes and lysosomes as well as organelle fusion. Here, we show that DABMA increases the endosomal TMEM175 current through organelle patch clamping with an EC₅₀ of 17.9 μm. Depletion of TMEM175 protein significantly decreases the antitoxin activity of DABMA and affects its action on acidic- and Rab7-positive endosomes as well as on endolysosomal trafficking. Thus, TMEM175 is necessary for DABMA's activity and may represent a druggable target for the development of anti-infective drugs. Moreover, DABMA, as an activator of the TMEM175 channel, may be useful for the in-depth characterization of the physiological and pathological roles of this endolysosomal channel.

Transforming growth factor-β (TGF-β) plays a complex role in lung cancer pathophysiology, initially acting as a tumor suppressor by inhibiting early-stage tumor growth. However, its role evolves in the advanced stages of the disease, where it contributes to tumor progression not by directly promoting cell proliferation but by enhancing epithelial-mesenchymal transition (EMT) and creating a conducive tumor microenvironment. While EMT is typically associated with enhanced migratory and invasive capabilities rather than proliferation per se, TGF-β's influence on this process facilitates the complex dynamics of tumor metastasis. Additionally, TGF-β impacts the tumor microenvironment by interacting with immune cells, a process influenced by genetic and epigenetic changes within tumor cells. This interaction highlights its role in immune evasion and chemoresistance, further complicating lung cancer therapy. This review provides a critical overview of recent findings on TGF-β's involvement in lung cancer, its contribution to chemoresistance, and its modulation of the immune response. Despite the considerable challenges encountered in clinical trials and the development of new treatments targeting the TGF-β pathway, this review highlights the necessity for continued, in-depth investigation into the roles of TGF-β. A deeper comprehension of these roles may lead to novel, targeted therapies for lung cancer. Despite the intricate behavior of TGF-β signaling in tumors and previous challenges, further research could yield innovative treatment strategies.

The paradigm that the vaginal microbiota is a protective gateway for the urinary and reproductive systems has endured for more than a century and driven decades of probiotic research. Evidence robustly supports the notion that healthy urogenital microbiomes are predominantly colonized by lactobacilli, particularly Lactobacillus crispatus, which can acidify the local environment and protect against urogynecologic pathogen colonization. However, recent studies are beginning to delve deeper into the intricate mechanistic interactions connecting the microbiome, its diverse functional potential, host immunity, pathogens, and the development of urogenital diseases. Leveraging these emerging insights alongside past successes presents promising opportunities for future therapies aimed at enhancing the management of conditions such as bacterial vaginosis, urinary tract infections, bladder pain, urinary incontinence, and beyond.

Pyruvate:quinone oxidoreductase (PQO) is a flavin-containing peripheral membrane enzyme catalyzing the decarboxylation of pyruvate to acetate and CO₂ with quinone as an electron acceptor. Here, we investigate PQO activity in Corynebacterium glutamicum, examine purified PQO, and describe the crystal structure of the native enzyme and a truncated version. The specific PQO activity was highest in stationary phase cells grown in complex medium, lower in cells grown in complex medium containing glucose or acetate, and lowest in cells grown in minimal acetate-medium. A similar pattern with about 30-fold higher specific PQO activities was observed in C. glutamicum with plasmid-bound pqo expression under the control of the tac promoter, indicating that the differences in PQO activity are likely due to post-transcriptional control. Continuous cultivation of C. glutamicum at dilution rates between 0.05 and 0.4 h^-1 revealed a negative correlation between PQO activity and growth rate. Kinetic analysis of PQO enzymes purified from cells grown in complex or in minimal acetate-medium revealed substantial differences in specific activity (72.3 vs. 11.9 U·mg protein^-1) and turnover number (k_cat: 440 vs. 78 s^-1, respectively), suggesting post-translational modifications affecting PQO activity. Structural analysis of PQO revealed a homotetrameric arrangement very similar to the Escherichia coli pyruvate oxidase PoxB except for the C-terminal membrane binding domain, which exhibited a conformation markedly different from its PoxB counterpart. A truncated PQO variant lacking 17 C-terminal amino acids showed higher affinity to pyruvate and was independent of detergent activation, highlighting the importance of the C-terminus for enzyme activation and lipid binding.

Obesity and obesity-related insulin resistance have been a research hotspot. Pituitary adenylate cyclase activating polypeptide (PACAP) has emerged as playing a significant role in energy metabolism, holding promising potential for attenuating insulin resistance. However, the precise mechanism is not fully understood. Palmitic acid and a high-fat diet (HFD) were used to establish insulin resistance model in Alpha mouse liver 12 cell line and C57BL/6 mice, respectively. Subsequently, we assessed the effects of PACAP both in vivo and in vitro. Lentivirus vectors were used to explore the signaling pathway through which PACAP may ameliorate insulin resistance. PACAP was found to selectively bind to the PACAP type I receptor receptor and ameliorate insulin resistance, which was characterized by increased glycogen synthesis and the suppression of gluconeogenesis in the insulin-resistant cell model and HFD-fed mice. These effects were linked to the activation of the Fas apoptotic inhibitory molecule/rapamycin-insensitive companion of mammalian target of rapamycin/RAC-alpha serine/threonine-protein kinase (FAIM/Rictor/AKT) axis. Furthermore, PACAP ameliorated insulin resistance by increasing solute carrier family 2, facilitated glucose transporter members 2/4 and inhibiting gluconeogenesis-related proteins glucose 6-phosphatase catalytic subunit 1 and phosphoenolpyruvate carboxykinase 2 expression. Meanwhile, the phosphorylation of hepatic AKT/glycogen synthase kinase 3β was promoted both in vivo and in vitro by PACAP. Additionally, PACAP treatment decreased body weight, food intake and blood glucose levels in obese mice. Our study shows that PACAP ameliorated insulin resistance through the FAIM/Rictor/AKT axis, presenting it as a promising drug candidate for the treatment of obesity-related insulin resistance.

AXIN1 and AXIN2 are homologous proteins that inhibit the Wnt/β-catenin signaling pathway, which is frequently hyperactive in colorectal cancer. Stabilization of AXIN1 and AXIN2 by inhibiting their degradation through tankyrase (TNKS) allows the attenuation of Wnt signaling in cancer, attracting interest for potential targeted therapy. Here, we found that knockout or knockdown of AXIN2 in colorectal cancer cells increased the protein stability of AXIN1. The increase in AXIN1 overcompensated for the loss of AXIN2 with respect to protein levels; however, functionally it did not because loss of AXIN2 activated the pathway. Moreover, AXIN2 was highly essential in the context of TNKS inhibition because TNKS-targeting small-molecule inhibitors completely failed to inhibit Wnt signaling and to stabilize AXIN1 in AXIN2 knockout cells. The increased AXIN1 protein stability and the impaired stabilization by TNKS inhibitors indicated disrupted TNKS-AXIN1 regulation in AXIN2 knockout cells. Concordantly, mechanistic studies revealed that co-expression of AXIN2 recruited TNKS to AXIN1 and stimulated TNKS-mediated degradation of transiently expressed AXIN1 wild-type and AXIN1 mutants with impaired TNKS binding. Taken together, our data suggest that AXIN2 promotes degradation of AXIN1 through TNKS in colorectal cancer cells by directly linking the two proteins, and these findings may be relevant for TNKS inhibition-based colorectal cancer therapies.

Upregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and a major cause of age-related chronic inflammation. However, its effect on cellular senescence remains unclear. Here, we show that alteration of NFκB nuclear dynamics from oscillatory to sustained by depleting a negative feedback regulator of NFκB pathway, NFκB inhibitor alpha (IκBα), in the presence of tumor necrosis factor α (TNFα) promotes cellular senescence. Sustained NFκB activity enhanced inflammatory gene expression through increased NFκB-DNA binding and slowed the cell cycle. IκBα protein was decreased under replicative or oxidative stress in vitro. Furthermore, a decrease in IκBα protein and an increase in DNA-NFκB binding at the transcription start sites of age-associated genes in aged mouse hearts suggested that nuclear NFκB dynamics may play a critical role in the progression of aging. Our study suggests that nuclear NFκB dynamics-dependent epigenetic changes regulated over time in a living system, possibly through a decrease in IκBα, enhance the expression of inflammatory genes to advance the cells to a senescent state.