Journal of Molecular Cell Biology最新文献

Early growth response (Egr) factors are involved in tissue development and repair. However, few studies have focused on the role of egr genes in renal regeneration after acute kidney injury (AKI) and the underlying mechanisms. In this study, we observed that egr1 and egr4 were sharply upregulated in wild type zebrafish at 1 day post-injury by gentamicin. Further experiments with egr1 and egr4 mutants showed that egr1 and egr4 were involved in zebrafish renal regeneration after AKI by regulating the proliferation and apoptosis of tubular cells. foxm1 is expressed in injured kidneys and involved in kidney repair. Loss of foxm1 inhibited zebrafish renal regeneration by decreasing the proliferation and increasing the apoptosis of tubular cells. Moreover, Egr1 and Egr4 promoted foxm1 expression by directly binding to the foxm1 promoter, thus regulating renal regeneration. Our results revealed that the rapid and transient induction of egr1 and egr4 after AKI exerts a renoprotective role through upregulating foxm1 to facilitate kidney regeneration. Therefore, the egr1/egr4-foxm1 regulatory axis holds a therapeutic potential for the treatment of AKI.

Colorectal cancer (CRC) is the third most prevalent malignancy worldwide and the second leading cause of cancer-associated deaths, posing a significant threat to human health. Given the limited therapeutic options and poor prognosis associated with CRC, there is an urgent need to develop new targeted therapeutic strategies to enhance clinical outcomes. The ubiquitin-proteasome system (UPS), a central regulator for cellular protein homeostasis, plays a pivotal role in the initiation and progression of CRC. The UPS modulates several essential signaling pathways and is involved in regulating tumor immunity and resistance to chemotherapy. Thus, the UPS contributes significantly to the complex biological processes underlying CRC pathogenesis. In recent years, small-molecule compounds targeting the UPS have exhibited considerable therapeutic potential in CRC treatment. These drugs intervene in crucial steps in the UPS, such as the activity of E1, E2, and E3 enzymes, or directly target the proteasome, thereby regulating the degradation of oncogenic proteins and effectively impeding tumor progression. Moreover, emerging therapeutic strategies such as proteolysis-targeting chimera (PROTAC) and molecular glue technologies selectively degrade specific oncogenic proteins, thereby offering new avenues and promising opportunities for CRC treatment.

RNA-binding motif protein 38 (Rbm38), also known as RNPC1, is a major regulator of post-transcriptional gene expression. It represents a potential candidate gene linked to the susceptibility of type 2 diabetes, and decreased RBM38 expression can enhance the proliferation of pancreatic cancer cells in humans. However, its role in pancreatic development remains elusive. In this study, we explored the function of Rbm38 using zebrafish as a model. Pancreatic expression of Rbm38 is present at larval stages and is controlled by several transcription factors acting on specific rbm38 promoter regions. The loss of Rbm38 leads to abnormal pancreatic enlargement. Mechanistically, Rbm38 is involved in several aspects of post-transcriptional regulation of pancreatic gene expression. It destabilizes pdx1 transcripts by binding to the 3'-untranslated region and regulates alternative splicing of key pancreatic transcription factor genes, including isl1a, smad2, and nkx2.2a. These findings elucidate the role of Rbm38 in pancreatic development and highlight its significance in maintaining pancreatic homeostasis.

SMAD4, a central mediator of the TGF-β signaling pathway, plays a critical role in regulating cellular processes such as proliferation, differentiation, and apoptosis. While SMAD4's canonical functions within TGF-β signaling are well-established, its non-canonical, TGF-β-independent roles remain poorly understood, particularly in the context of disease biology. Here, we investigate SMAD4's TGF-β-independent functions by identifying and characterizing its protein-protein interaction network. Using pancreatic ductal adenocarcinoma as a model system, we performed a SMAD4-focused oncogenic protein-protein interaction mapping and uncovered a novel interaction between SMAD4 and NFATc1. We demonstrated that SMAD4 binds to NFATc1 in a phosphorylation-dependent but TGF-β-independent manner, sequestering NFATc1 in the cytoplasm and inhibiting its transcriptional activity. The absence of this interaction in SMAD4-deficient PDAC cells is associated with the activation of NFATc1 transcriptional programs and upregulation of STAT3 at both mRNA and protein levels. Pharmacological profiling revealed multiple STAT3 inhibitors with selective efficacy against SMAD4-deficient PDAC cells in vitro, highlighting a potential therapeutic vulnerability. These findings identify a previously uncharacterized SMAD4-NFATc1 regulatory complex and establish its biological significance in regulating NFATc1-driven transcriptional programs, such as STAT3, providing critical insights into SMAD4's TGF-β-independent functions and uncovering new opportunities for therapeutic intervention in SMAD4-deficient contexts.

Individuals with diabetes are at high risk of fragility fractures. We aimed to develop and validate a protein-based model to predict fragility fractures in individuals with diabetes and to explore whether a protein risk score (ProRS) would improve the risk prediction. A total of 3535 individuals with diabetes from the UK Biobank Pharma Proteomics Project were included in the study. During a median follow-up period of 13.3 years, 5.2% (185) of the individuals with diabetes experienced a fragility fracture. Of 2902 unique proteins, 139 exhibited significant associations with fragility fracture risk. A protein-based model that included 10 proteins was then developed using the machine learning model. Compared with the low ProRS tertile, medium and high tertiles were strongly associated with increased fragility fracture risk. The ProRS achieved a C-index of 0.739 and a 10-year area under the curve (AUC) of 0.733 for the fragility fracture prediction. Adding ProRS to the traditional prediction model (the fracture risk assessment tool [FRAX]) improved the prediction performance with a C-index increase of 0.080 (0.673 [FRAX] versus 0.754 [FRAX + ProRS]) and a 10-year AUC increase of 0.064 (0.693 versus 0.757), thereby promoting early monitoring and prevention in individuals with diabetes.

Overweight and obesity are major global health challenges. Despite progress in behavioral interventions, nutrition, physical activity, pharmacotherapy, and bariatric procedures, weight regain (WR) after successful weight loss is a major challenge. Understanding the definition and physiological mechanisms of WR is crucial for developing effective strategies to tackle weight regain and reduce cardiometabolic disorders. This review summarizes recent advances in weight loss strategies. We also discuss the metrics used to quantify WR, emphasizing the need for standardization to facilitate comparison between studies, and examine WR predictors including demographic and clinical characteristics, behavior, anatomic factors, and biological markers. The potential physiological mechanisms underlying WR, focusing on obesity memory, metabolic adaptation, and gut hormone alterations are further elucidated. Comprehensively understanding WR provides a foundation for developing long-term, personalized strategies and integrating emerging technologies such as artificial intelligence into long-term weight management.

The endoplasmic reticulum (ER) lipid raft proteins (Erlins) belong to the stomatin-prohibitin-flotillin-HflC/K (SPFH) family and form highly oligomeric platforms that mediate the degradation of activated inositol 1,4,5-trisphosphate receptors by facilitating their interaction with the E3 ligase RNF170. However, the molecular mechanisms underlying this process remain unclear. Here, we successfully reconstituted the Erlin1-Erlin2 complex and its complex with RNF170 by overexpressing these components in HEK293F cells. We also isolated the Erlin2 oligomer by solely expressing Erlin2 in the cells. Using cryo-EM, we determined the structures of the Erlin1-Erlin2 complex, Erlin1-Erlin2-RNF170 complex, and Erlin2 oligomer at resolutions of 3.29 Å, 3.05 Å, and 2.12 Å, respectively. Both the Erlin1-Erlin2 complex and the Erlin2 oligomer exhibit similar cage-like architectures, with the Erlin1-Erlin2 complex containing 13 pairs of Erlin1 and Erlin2 subunits, whereas the Erlin2 oligomer comprises 26 Erlin2. Although RNF170 was clearly identified during protein purification, it was invisible in the final 3D reconstruction, suggesting a high degree of flexibility between RNF170 and the Erlin complex. Multiple water molecules were identified in the Erlin2 oligomer, underscoring their critical roles in facilitating the high degree of oligomerization of the Erlin2 complex. Taken together, our structural investigation elucidates the molecular basis for the assembly of the Erlin complex and provides a framework for further investigation.

The parathyroid gland, a pivotal organ regulating calcium and phosphorus homeostasis, harbors two primary cell types: chief cells and the enigmatic oxyphil cells. While scarce in healthy individuals, oxyphil cells undergo pronounced proliferation in uremic secondary hyperparathyroidism (SHPT), and their abundance is strongly associated with resistance to first-line therapies like calcitriol and calcimimetics. This correlation underscores a critical clinical challenge, yet the origin, functional role, and mechanisms driving oxyphil cell proliferation have remained poorly understood. Integrated multi-omics studies have decisively illuminated the underlying mechanisms, revealing uremic milieu-driven transdifferentiation from chief cells to oxyphil cells and the pivotal role of mitochondrial biogenesis activation in this process. This paradigm shift redefines oxyphil cells from passive entities to metabolically hyperactive, autonomous units capable of heightened parathyroid hormone synthesis and secretion. The core mechanism of therapy resistance is explained by the profound downregulation of key regulatory receptors, rendering them insensitive to conventional drugs. This review synthesizes current knowledge and, more importantly, highlights how integrated multi-omics approaches are illuminating the pathobiology of oxyphil cells, providing groundbreaking insights into their function, origin, and proliferation mechanisms. We conclude that these advances are pivotal for developing novel therapeutic strategies to overcome treatment resistance in uremic SHPT.

Double-negative T (DNT) cells (TCRαβ+CD4-CD8-NK1.1-/CD56-) exhibit strong tumor-killing capabilities. Our single-cell transcriptome analysis has revealed high Fcer1g expression in DNT cells, but its role in tumor immunity remains unclear. In this study, we demonstrated that IgG1 stimulation significantly upregulated IgG Fc receptors and cytotoxic molecules in DNT cells, enhancing their cytotoxicity against MC38 tumor cells in vitro. Fcer1g-deficient DNT cells failed to respond effectively to IgG1 stimulation. Inhibiting the downstream spleen tyrosine kinase (Syk) of FcεRIγ reduced cytotoxicity of DNT cells and phosphorylation levels of molecules such as AKT and NF-κB. In a subcutaneous tumor model, combined treatment with DNT cells and tumor-specific antibodies more effectively inhibited tumor growth compared to DNT cells alone, while Fcer1g-deficient DNT cells combined with antibodies showed no significant difference in efficacy compared to DNT cells alone, suggesting that DNT cells enhance tumor cell killing via FcεRIγ-mediated antibody-dependent cellular cytotoxicity (ADCC). These results indicate that DNT cells mediate antitumor ADCC effects through high FcεRIγ expression. Binding of IgG1 to FcεRIγ activates the FcεRIγ/Syk/AKT/NF-κB pathway, consequently enhancing tumor cell killing. Thus, DNT cells may play a significant role in cancer immunity, providing a basis for novel immune cell and antibody combination therapies.