Cellular and Molecular Life Sciences最新文献

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disorder with increasing incidence globally. However, the understanding of UC pathogenesis remains limited.

Methods: DSS-induced UC mouse model and lipopolysaccharide (LPS)-treated colonic epithelial cell (CEC) model were established. The pathological changes in colons were evaluated by hematoxylin and eosin. Colon injury was graded by pathological scoring, evaluation of colon length and disease activity index. qRT-PCR, Western blot, immunofluorescent staining, and ELISA assay were used to detect the expression and secretion of key molecules. CCK-8 was employed to monitor cell viability. The m⁶A modification of phosphoglycerate dehydrogenase (PHGDH) was assessed by MeRIP assay, and the SUMOylation of PHGDH, as well as the association between PHGDH and ubiquitin conjugating enzyme 9 (UBC9), were detected by co-immunoprecipitation.

Results: PHGDH knockdown alleviated DSS-induced colitis in mice. Inhibiting PHGDH promoted autophagy and inhibited inflammation in DSS-induced colitis and LPS-treated CECs. Methyltransferase-like 3 (METTL3) mediated m⁶A modification of PHGDH in LPS-treated CECs. PHGDH overexpression reversed METTL3 knockdown-facilitated autophagy in the in vitro UC model. Additionally, UBC9-mediated SUMOylation regulated PHGDH protein stability in vitro. Enhanced SUMOylation of PHGDH rescued LPS-impaired cell viability via promoting autophagy. METTL3 inhibited autophagy in LPS-treated CECs by regulating UBC9/PHGDH axis. METTL3 knockdown and UBC9 overexpression synergistically alleviated DSS-induced colon injury. Furthermore, curcumin promoted autophagy via modulating METTL3/UBC9/PHGDH axis, thereby alleviating colonic damage in ulcerative colitis.

Conclusion: m⁶A modification and SUMOylation of PHGDH regulated UC through Beclin-1-dependent autophagy.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease characterized by the accumulation of cholestanol. CTX patients often suffer from cognitive impairment. We found that serum cholestanol levels are higher in Alzheimer's disease (AD) patients than in control subjects. Thus, we tested whether cholestanol regulates the pathogenesis of AD. Cholestanol promotes tau fragmentation and hyperphosphorylation by activating asparagine endopeptidase (AEP). AEP knockdown alleviates cholestanol-induced tau fragmentation and phosphorylation. Feeding cholestanol to tau P301S mice aggravates tau pathology and behavioral defects, while knockout of AEP ameliorates cholestanol-induced tau pathology and behavioral defects in tau P301S mice. These results highlight the role of AEP-mediated tau cleavage in cholestanol-induced tau pathology and cognitive decline. The data also identify the potential therapeutic target of AEP in AD, particularly in AD patients with elevated serum cholestanol levels.

Complement factor C3 is one of the most abundant proteins in the bloodstream and a central part of the complement system. Upon activation, C3 facilitates bacterial recognition and clearance in the extracellular environment. Initially regarded as a serum effector component, C3 is also emerging as an intracellular protein regulating basic cellular processes. Previously, we reported that intracellular, cytosolic C3 can opsonize bacteria and impact their virulence. In this study, we show that cells lacking C3 exhibit altered gene expression that influences immune responses to infection and inflammation. We observed decreased cytokine secretion in C3-deficient cells, which was rescued by expression of non-canonical, cytosolic C3. Further investigation revealed that C3 deficiency impairs signal transduction within the NF-κB signaling pathway, which is attributed to decreased expression of Toll-like receptors. This effect is reversed in cells expressing cytosolic C3, where receptor expression and pathway activation are restored. Therefore, we propose a novel role of intracellular, cytosolic C3 in shaping immune responses by modulating the expression of receptors critical to pathogen recognition.

Plasma membrane rupture (PMR), once considered a passive event in necrosis, is actively executed by ninjurin-1 (NINJ1). Although PMR is a well-documented phenomenon across animal species, its molecular mechanism and immunological function in early diverging jawed vertebrates remain unclear. Herein, we identify a functional homolog of NINJ1 in turbot. Ectopic expression of turbot NINJ1 effectively lyses the plasma membrane, leading to rapid PMR and massive release of cellular contents. Given that turbot NINJ1 has two transmembrane helices, it could distribute within membrane-bound organelles and the plasma membrane as PMR progresses. Co-expression with turbot gasdermin significantly amplifies NINJ1-mediated PMR, even when both proteins are present at non-cytotoxic levels. Structural analysis reveals the importance of its extracellular and transmembrane helices, with specific functional residues crucial for its PMR-inducing activity. Bacterial infection upregulates NINJ1 and activates pyroptosis signaling pathway, and provokes strong proinflammatory responses. Inhibiting NINJ1 improves fish survival, whereas blocking pyroptosis actually dampens host antimicrobial immunity. Collectively, the present findings delineate a mechanistically distinct role of NINJ1 in regulating programmed cell death in turbot, highlighting the complex and bifunctional nature of cell death in teleost immunity.

Microglia, the resident immune cells in the retina, play important roles in the retinopathies. Although the role of the Notch signaling pathway in microglial activation and inflammation in neuroinflammatory diseases has been extensively studied, less is known about the effects of Notch signaling on retinal microglia in ischemic retinopathies. Here, we demonstrated that hypoxia triggers Notch1-FoxO1 nuclear translocation in retinal microglia, driving proinflammatory and proangiogenic phenotypes that disrupt vascular homeostasis. We first showed that hypoxia induced microglial activation and upregulated the levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α and proangiogenic factors FGF2, VEGF, and PDGF-β, which promoted retinal vascular endothelial cell dysfunction, marked by increased cellular permeability, migration, and tube formation. We then identified the Jagged1-Notch1 pathway and FoxO1 nuclear translocation as a pivotal signaling axis driving this proinflammatory microglial response under hypoxia. Finally, we demonstrated the therapeutic potential of this axis by showing that inhibition of Notch1 or FoxO1 in hypoxia-activated microglia and in the eyes of oxygen-induced retinopathy mice ameliorated both inflammation and pathological neovascularization in the retina. These findings suggest that FoxO1, together with Notch1, promotes microglial activation to induce retinal vasculopathy under hypoxia, indicating that targeting the Notch1-FoxO1 axis may be a therapeutic strategy for ischemic retinopathies.

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. It plays a crucial role in various pathological conditions, including neurodegenerative diseases, cancer, ischemia-reperfusion injury, and organ failure. This review systematically explores the key mechanisms underlying ferroptosis, including polyunsaturated fatty acid-containing phospholipid (PUFA-PL) peroxidation, iron metabolism, and mitochondrial dysfunction. Additionally, we summarize major endogenous ferroptosis defense systems, including the SLC7A11-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, the ferroptosis suppressor protein 1 (FSP1)-ubiquinol (CoQH₂) system, the mitochondrial dihydroorotate dehydrogenase (DHODH)-CoQH₂ pathway, and the guanosine triphosphate cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway, which act as critical brakes on ferroptosis. Furthermore, we discuss various small-molecule inhibitors targeting ferroptosis, categorized by their mechanisms of action, including iron chelators, lipid peroxidation inhibitors, antioxidants, and regulatory pathway modulators. Recent advances in pharmacological strategies and their potential therapeutic applications are also highlighted.

Acute myeloid leukemia (AML) is a heterogenous disease characterized by the accumulation of immature myeloid blasts with distinct genetic mutations in the bone marrow and peripheral blood. AML co-evolve with other components of specialized bone marrow niches within a microenvironment enriched in cytokines and inflammatory cells; among these, interleukin-1 (IL-1) may act as a tumor driver. This review examines two complementary aspects of AML biology in relation to IL-1. First, we describe the functional activity of IL-1 and the signaling pathways triggered by the IL-1 receptor in malignant cells, along with preclinical and clinical studies targeting this pathway in AML. Second, we discuss the mechanisms regulating the release of mature IL-1β through the activation of different inflammasomes. Inflammasomes, particularly NLRP3, are emerging as key contributors to AML pathophysiology. Beyond IL-1 release, NLRP3 may interface with cellular stress responses and pyroptosis, thereby influencing both AML cells and their microenvironment through multiple mechanisms. Inflammasome signaling may act as a driver of therapy resistance while also representing a promising therapeutic target.

Polarized cell growth necessitates the dynamic remodeling of the plasma membrane, a process requiring BAR domain-containing proteins. While classical BAR proteins, with their crescent-shaped structure, are well characterized, the mechanisms underlying the localization and function of elongated F-BAR proteins remain unclear. Here, we demonstrate that the F-BAR domains of the fission yeast proteins Rga7 and Rga8 undergo liquid-liquid phase separation (LLPS). These domains form oligomers via hydrophobic interactions and assemble into condensates through electrostatic interactions mediated by the charged residues at their tips. Mutants deficient in phase separation fail to localize properly at cell poles, leading to defective polar distribution of key regulators, including the Rho GTPases, the exocyst complex, and glucan synthases, all crucial for maintaining cell integrity. We further show that Rga8 requires the actin transport system for tip localization, whereas Rga7 accumulates at cell tips via diffusion. The absence of both Rga7 and Rga8 causes cell lysis. Hence, our findings establish LLPS as a fundamental mechanism for the cortical accumulation and function of F-BAR proteins, providing new insights into their role in membrane dynamics.