Journal of Molecular Cell Biology最新文献

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.

Fam3C, also known as Interleukin-like EMT inducer (ILEI), is an established regulator of the epithelial to mesenchymal transition and breast cancer stem cell phenotypes. Multiple cancer cell models and orthotopic animal model experiments have demonstrated a role for Fam3C in tumor progression and metastasis. Here, we establish Fam3C's impact on triple negative breast cancer patients and genetically engineered mouse models of spontaneous breast cancer tumor progression. Though Fam3C is a known secreted protein, we discovered its retention in the Golgi apparatus through anchoring of its signal peptide into the membrane before its signal peptide and pro-peptide are processed and removed. While retained in the Golgi apparatus, Fam3C affects the overall morphology of the organelle and its biological functions, including alterations in protein secretion and invasive potential. Expanding our knowledge of the biological mechanisms behind EMT will help develop therapies to specifically target cells with increased metastatic potential in triple negative breast cancer.

HSF-1 is a highly conserved transcription factor that plays a central role in protecting organisms from diverse cellular stresses. However, the mechanisms by which HSF-1 senses and responds to different types of stress remain incompletely understood. COPII-coated vesicles, responsible for transporting cargo from the endoplasmic reticulum to the Golgi apparatus, are essential for protein secretion and cellular homeostasis. Disruption of these vesicles impairs protein secretion and triggers severe proteotoxic stress. Here, we show that HSF-1 directly monitors COPII vesicle dysfunction through interactions with the core COPII component SEC-23, in both Caenorhabditis elegans and NIH3T3 cells. Inhibition of SEC-23 or SAR-1 disrupts COPII vesicle formation, leading to the release of HSF-1 from the COPII complex. This release induces a specific transcriptomic change to restore protein homeostasis. Our findings reveal a conserved mechanism by which HSF-1 responds to COPII vesicle dysregulation, providing new insights into the HSF-1-centered proteostasis network.

Kawasaki disease (KD) is an acute febrile systemic vasculitis associated with the development of coronary artery lesion and coronary artery aneurysm. This condition is characterized by sustained vascular inflammation and endothelial dysfunction, in which pyroptosis serves as a pivotal driver of inflammatory response. However, the molecular mechanisms linking pyroptosis to endothelium injury and KD pathogenesis remain poorly understood. Analysis of public datasets revealed a marked decrease in T-cadherin (T-cad, CDH13) expression in cardiac tissues from KD patients and KD model mice compared to controls. In vitro and in vivo experiments revealed the reduced T-cad expression in both the treated human umbilical vein endothelial cells (HUVECs) and the abdominal aorta of Lactobacillus casei cell wall extract (LCWE)-induced KD mice. RNA sequencing analysis of HUVECs with siRNA-mediated T-cad knockdown showed significant enrichment of genes involved in pro-inflammatory cascades and pyroptosis-associated pathways. Western blot analysis further validated the upregulation of pyroptosis-associated proteins, including NLRP3, caspase-1, GSDMD, IL-1β, and IL-18, in the T-cad knockdown group compared to controls. These findings were supported by functional assays demonstrating the increased lactate dehydrogenase release, higher TUNEL-positive cells, and elevated reactive oxygen species (ROS) levels in the T-cad knockdown group. Collectively, our results indicate that inflammatory stimuli downregulate T-cad expression in endothelial cells, subsequently reducing superoxide dismutase 2 (SOD2) expression and its enzymatic activity. This leads to ROS accumulation, which activates the NLRP3 inflammasome and initiates pyroptosis. Thus, T-cad deficiency induces pyroptosis in HUVECs via the activation of the SOD2/ROS/NLRP3 pathway. These findings highlight the pivotal role of T-cad deprivation-mediated endothelial cell pyroptosis in the initiation and progression of KD, providing novel insights into its pathophysiology and potential therapeutic targets.

Cells sense and respond to forces from neighbouring cells and the extracellular matrix during growth and division. When cells undergo mitosis in a confined environment like in the tumour environment, high compressive stress causes unstable cell cortex and prolonged mitosis. Confined mitotic cells frequently experience chromosome loss and multipolar division. How the cortical instability affects cytokinesis under confinement is unclear. Here, we show that confined mitotic cells undergo furrow ingression comparable to unconfined mitotic cells but are strongly reliant on Aurora B kinase, a catalytic subunit of the chromosomal passenger complex (CPC) for its completion. Mechanistically, the cortical pool of CPC via the scaffolding protein INCENP sustains Aurora B at the equatorial cortex to drive furrow ingression under confinement. We identified mechanoresponsive elements within the single alpha-helix domain of INCENP that maintain the cortical CPC at the equatorial cortex to promote furrow ingression in response to high compressive stress. Thus, the cortical INCENP not only binds to actin filaments but also mechanically responds to forces at the equatorial cortex to regulate the CPC during confined cytokinesis.