Journal of Molecular Cell Biology最新文献

Mutations in ribosome biogenesis-related genes or functional defects in ribosomal proteins can lead to a class of autosomal genetic disorders characterized by tissue-specific defects, termed ribosomopathies. NOC4L, a critical factor in ribosome biogenesis, participates in the maturation of the 40S small ribosomal subunit. However, its functions in neural and cartilage development remain incompletely understood. In this study, through generation and phenotypic characterization of a zebrafish noc4l knockout model, we identified severe developmental abnormalities including microcephaly, micrognathia, and embryonic lethality. Further analyses revealed that noc4l loss-of-function results in reduced proliferation, differentiation blockade, and apoptotic activation. Mechanistically, sucrose gradient analysis demonstrated the disrupted ribosome biogenesis in noc4l mutants, with significantly reduced 40S/80S subunits and polysome levels, ultimately leading to overall translational inhibition and concurrent suppression of metabolic pathways. Pharmacological PPARγ activation via rosiglitazone partially rescued craniofacial malformations, ameliorated neurodevelopmental defects, and prolonged mutant life span. Although inhibition of the p53 pathway can partially rescue the phenotype, the p53 pathway and metabolic pathways are likely independent contributing factors. Our study reveals the molecular basis of developmental defects in noc4l mutants through impaired ribosome assembly and demonstrates the therapeutic potential of metabolic interventions for ribosomopathies.

Tumorigenesis exhibits complex interactions with the vascular system. Targeting angiogenesis represents an emerging strategy for remodeling the tumor microenvironment. The Notch signaling pathway, a key regulatory mechanism, orchestrates tumor angiogenesis by modulating endothelial cell differentiation and vascular homeostasis. However, the clinical translation of Notch-targeted therapies is limited by severe toxicities due to lack of tissue specificity. Posttranslational modifications (PTMs) chemically regulate protein functions, thereby influencing multiple signaling cascades including Notch signaling. Notably, Notch-associated PTMs are essential for signal transduction integrity. Some types in PTMs, such as glycosylation and ubiquitination, are the core for maintaining the integrity of the Notch signaling pathway. Dysfunctional Notch-related PTMs disrupt signal fidelity and drive pathological angiogenesis. This review systematically explores: (i) crosstalk between Notch signaling and tumor angiogenesis, (ii) regulatory roles of PTMs on Notch molecules in tumor angiogenesis, and (iii) therapeutic potential of targeting Notch-related PTMs for anti-angiogenic strategies in tumor. We aim to elucidate the molecular nexus of PTMs-Notch-angiogenesis in tumor progression. Furthermore, we discuss therapeutic challenges in modulating Notch signaling pathway-dependent PTMs within tumor angiogenesis, focusing on critical barriers to their clinical translation in oncology.

The canonical Wnt/β-catenin pathway critically regulates cardiac calcium homeostasis, yet its interplay with microenvironmental factors remains unclear. This study reveals that fetal bovine serum (FBS) treatment alters Wnt-mediated calcium dynamics in AC16 cardiomyocytes. While Wnt activation elevates cytosol calcium in serum-free conditions, FBS supplementation reverses this response: Wnt inhibitors (SFRP2, XAV939, and LF3) induce cytosol calcium accumulation, while the activators (LiCl and Wnt3a) lose efficacy. Mechanistically, FBS ablates RyR2 expression, uncoupling calcium-induced calcium release. Consequently, calcium handling shifts to SERCA2a-dependent regulation. We identify myoregulin (MLN) as a pivotal effector of the Wnt/β-catenin signaling with Wnt inhibition upregulating MLN to suppress SERCA2a activity. MLN knockdown (90% suppression) abolishes the effects of Wnt inhibitors on SERCA2a function and calcium distribution patterns. RyR2 reconstitution in FBS-treated cells restores calcium release but not Wnt activation responses, confirming the dominant role of MLN. Crucially, a combination of RyR2 overexpression and MLN depletion fully restores Wnt-calcium responses, phenocopying serum-free conditions. Our work establishes a serum-dependent regulatory axis where Wnt/β-catenin signaling maintains calcium homeostasis by repressing MLN, thereby preserving SERCA2a function. This FBS-induced shift mirrors pathological adaptations in heart failure, positioning MLN as a therapeutic target for calcium-handling disorders.

Emerging evidence implicates tumor stemness features-characterized by self-renewal capacity, microenvironment adaptability, and immune evasion mechanisms-as critical determinants of therapeutic resistance and recurrence in hepatocellular carcinoma (HCC). KCNJ12, an inward rectifier potassium channel, has shown electrophysiological functions in cardiomyocytes; however, its oncogenic potential and the role in hepatocarcinogenesis involving cancer stemness regulation remain unexplored. This study systematically characterizes the KCNJ12-mediated molecular pathway driving HCC tumorigenicity. Lentiviral-mediated overexpression and knockdown models with functional assessments revealed KCNJ12's critical role in maintaining cancer cell self-renewal capacity. Mechanistic studies using cycloheximide chase assays, Wnt pathway modulators (LiCl, SKL2001, and Salinomycin), and protein interaction analyses demonstrated that KCNJ12 stabilizes β-catenin through the physical interaction with lipoprotein receptor-associated protein 6 (LRP6), disrupting AXIN/APC/GSK-3β complex assembly and subsequent proteasomal degradation. The nuclear β-catenin accumulation drives TCF/LEF-dependent transcriptional activation and thus enhances the self-renewal capacity of HCC cells. Our findings establish KCNJ12 as a novel Wnt/β-catenin regulator and propose dual therapeutic strategies against HCC-mediated chemoresistance: pharmacological suppression of KCNJ12 channel activity and targeted disruption of KCNJ12-LRP6 protein interactions. This mechanistic framework advances our understanding of stemness regulation in HCC and provides feasible targets for developing next-generation anti-HCC therapies.

Mitochondria are essential organelles responsible for generating ATP through oxidative phosphorylation (OXPHOS). Despite having their own genome, mitochondria rely on a complex interplay with nuclear-encoded proteins to maintain their function, as mutations in these proteins can lead to mitochondrial dysfunction and associated diseases. Mutations in the SLIRP (stem-loop interacting RNA-binding protein) gene are known to cause severe human mitochondrial diseases, and loss of SLIRP function can impair mitochondrial mRNA stability and translation. However, in vivo roles of the SLIRP protein remain inadequately understood. Drosophila melanogaster serves as a powerful model for studying mitochondrial function, particularly in the context of reproductive system development and gametogenesis. In this study, we focus on the role of the fly Slirp2 in oogenesis. Loss of Slirp2 impairs mitochondrial protein synthesis, leading to reduced OXPHOS efficiency, diminished ATP production, and disrupted insulin/mTOR signaling. These defects ultimately promote reactive oxygen species-induced programmed cell death, resulting in infertility. Our findings provide novel insights into the mechanistic role of Slirp2 in mitochondrial function and reproductive biology in vivo. We demonstrate that Slirp2 exhibits species-specific regulation of mitochondrial translation, revealing its complex, context-dependent function. These results have broader implications for understanding mitochondrial diseases, suggesting that the effects of Slirp2 mutations may vary across different organisms and tissue types.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic condition, yet therapeutic targets remain elusive. Nicotinamide phosphoribosyl transferase (NAMPT) and six-transmembrane epithelial antigen of the prostate 4 (STEAP4) are integral regulators in various metabolic disorders. This study investigates the role and molecular mechanisms of NAMPT in NAFLD pathogenesis. We found that inhibiting NAMPT or knockdown of silent information regulator 1 (SIRT1) exacerbates liver steatosis and impairs hepatic antioxidant defenses in high-fat diet (HFD)-induced obese mice, while reducing STEAP4 expression, suggesting that NAMPT and SIRT1 are pivotal in NAFLD progression and may regulate STEAP4. The role of NAMPT in SIRT1 expression involves nicotinamide adenine dinucleotide (NAD) synthesis. Our results indicate that inhibiting SIRT1's deacetylase activity impairs CCAAT/enhancer-binding protein β (C/EBPβ) deacetylation and consequently its function. Additionally, STEAP4, previously identified as a C/EBPβ target, can upregulate the expression and nuclear translocation of NF-E2-related factor 2 (NRF2) to combat oxidative stress in NAFLD. This study confirms that NAMPT ameliorates NAFLD via the SIRT1-C/EBPβ-STEAP4-NRF2 signaling axis in HFD-induced obese mice, proposing a novel strategy for the prevention and treatment of NAFLD.

The transcription factor ZBTB7B has been identified as a potential tumor suppressor through a CRISPR-Cas9-based functional screen of tumor-associated genes, as overexpression of ZBTB7B could significantly suppress tumor growth in the models of breast cancer brain metastasis, which prompted our further exploration of its inhibitory role in glioma. To elucidate the underlying mechanisms of this suppressive effect, lentiviral-mediated ZBTB7B overexpression was established in U118 and GL261 glioma cell lines, and systematic evaluation of tumorigenic capacity was performed through in vitro and xenograft assays. The results showed that ZBTB7B transcriptionally activated GPR17 expression, which suppressed protein kinase A phosphorylation, amplified mitochondrial reactive oxygen species generation, and triggered Caspase3-dependent apoptosis. Meanwhile, ZBTB7B upregulated CXCL10 secretion, which markedly enhanced CD4+ and CD8+ T cell accumulation. Clinical validation through multiplex immunofluorescence staining on a tissue microarray of 129 glioma samples revealed a progressive loss of ZBTB7B protein expression across WHO grades II to IV, inversely correlating with tumor malignancy. These findings demonstrate ZBTB7B as a dual-function tumor suppressor that concurrently induces intrinsic apoptosis and remodels the tumor immune microenvironment in glioma toward a 'hot' phenotype. Therefore, we propose ZBTB7B reactivation as a novel therapeutic strategy for glioma.

The mechanism underlying the selective loss of dopaminergic neurons in Parkinson's disease (PD) is still not understood at present. MPTP, an illicit drug contaminant, can selectively induce parkinsonism in humans and animals which is very similar to idiopathic PD. Like MPTP, 6-hydroxydopamine (6-OHDA) is another neurotoxicant also capable of selectively inducing parkinsonism in animal models. In this paper, a unifying hypothesis is proposed, which offers a plausible explanation for the pathogenic mechanism of parkinsonism induced by MPTP and 6-OHDA. This hypothesis has three core elements: (i) The vesicular monoamine transporter 2 (VMAT2) is the transporter responsible for the reverse transport (efflux) of the misplaced cytosolic dopamine (DA). (ii) Activation of VMAT2-mediated DA reverse transport is caused by elevated oxidative stress, often resulting from the buildup of cytosolic DA in dopaminergic neurons. (iii) VMAT2 is a major target of MPP+ (a toxic metabolite of MPTP) and 6-OHDA, and inhibition of VMAT2-mediated DA reverse transport by MPP+ or 6-OHDA will result in the buildup of cytosolic DA, and its subsequent oxidation/auto-oxidation will further heighten oxidative stress and generate chemically-reactive, neurotoxic DA derivatives. These DA-associated oxidative changes jointly contribute to the selective injury to dopaminergic neurons and the induction of parkinsonism. This mechanistic hypothesis agrees with a large body of experimental observations, and also offers a mechanistic explanation for many experimental findings. Additionally, this hypothesis offers mechanistic insights into the pathogenic role of α-synuclein in human PD based on its strong ability to suppress VMAT2-mediated DA reverse transport in dopaminergic neurons.