Journal of Molecular Cell Biology最新文献

The role of inflammation in psychiatric disorders, such as anxiety, has gained increasing attention, with the hippocampus being identified as a key region involved in emotional regulation. Argon has been reported to alleviate the symptoms of psychiatric disorders; however, its underlying mechanism remains unclear. In this study, we found that argon significantly suppressed lipopolysaccharide-induced anxiety-like behaviors and attenuated hippocampal neuronal hyperexcitability in mice. By analyzing neuronal excitability following microglial depletion and subsequent repopulation, as well as assessing microglial morphology, we confirmed that microglia are key targets of inflammation and validated the inhibitory effects of argon. Electrophysiological studies and transcriptome sequencing revealed that argon inhibited the microglia-released inflammatory cytokines via the Toll-like receptor 4/nuclear factor-κB signaling pathway, thereby improving the excitability of hippocampal neurons. Collectively, this study provides evidence that the regulation of microglia may be the underlying mechanism by which argon ameliorates neuroinflammation-induced anxiety-like behaviors.

Telomeric repeat-containing RNA (TERRA) is a class of non-coding RNAs emanating from telomeres and controlling telomere dynamics. Recent studies showed that TERRAs influence chromatin structure and gene expression. TERRAs can also play a crucial role in controlling inflammation, oxidative stress, DNA damage, and cellular senescence. This review discusses the significance of TERRAs in modulating these processes, particularly in the central nervous system (CNS). While our understanding of TERRAs largely stems from cancer research, their involvement in these physiologic and pathologic pathways highlights their potential as therapeutic targets for CNS disorders as well.

ADP-ribosylation factor (Arf)-specific GTPase-activating proteins (ArfGAPs) regulate cell migration through interactions with small G proteins, including Arfs. In ArfGAPs, the Bin/Amphiphysin/Rvs (BAR) domain plays a key role in membrane binding and curvature induction, yet the molecular mechanisms underlying these processes remain unclear. Here, we investigate the function of the BAR domain and its adjacent pleckstrin homology (PH) domain of ACAP4 in cell migration. We demonstrate that the BAR-PH tandem of ACAP4 induces membrane curvature, promotes cell migration, forms condensates in vitro, and exhibits membrane-associated distribution in cells. The crystal structure of the ACAP4 BAR domain, determined at 2.8 Å resolution, reveals multiple positively charged surface patches. Structural modeling further identifies conserved positively charged residue pairs in the PH domain, which collectively mediate electrostatic interactions essential for both membrane remodeling and membrane localization. Mutagenesis experiments confirm that these regions are required for ACAP4's subcellular localization and pro-migratory activity. Furthermore, we identify that the actin-binding protein Ezrin interacts with a specific C-terminal region of ACAP4 to regulate its function. Ezrin binding enhances condensate formation and enables full-length ACAP4 to associate with membranes and promote cell migration, particularly when co-expressed with the activated Ezrin (T567D). Together, our findings uncover the molecular basis by which ACAP4 coordinates membrane remodeling and cytoskeletal dynamics, offering new insights into the mechanisms that drive cell migration.

Obese individuals even with normal glucose tolerance (NGT) are at higher risk for developing type 2 diabetes (T2D), and obesity is associated with inflammation. However, mechanisms linking inflammation to beta-cell function and insulin sensitivity in NGT individuals are not fully understood. We aimed to investigate the relationships between inflammation-related proteins (IRPs) and insulin dynamics in NGT subjects. The explorations were conducted using data from 1109 non-diabetes subjects aged 40-44 with normal or excess body weight and 21 Chinese NGT subjects aged 22-32 with accurate metabolic assessment. IRPs were detected with Olink technology. Insulin sensitivity and beta-cell function were evaluated with hyperinsulinemic-euglycemic clamp and hyperglycemic clamp. Eight associators were identified with obesity in NGT subjects, among which MCP-3, IL-6, TWEAK, HGF, and CST5 also showed associations in non-diabetes people. Four IRPs were linked to insulin sensitivity, with IL-24 being a novel finding. Seven IRPs were related to beta-cell function, including novel associators CD244, CD40, and IL-15RA. Moreover, most IRPs were interconnected, with IL-6 as the hub. In conclusion, insulin sensitivity and beta-cell function are related to IRPs involved in chemotaxis, activation of immune cells, and cell proliferation, which might provide valuable information for the understanding of the mechanisms associated with T2D pathogenesis.

Flaviviridae Dengue virus (DENV) and Zika virus (ZIKV) have posed significant threats to global public health in the past decades. Despite extensive study on therapeutic strategies against these viruses, effective treatment options are still lacking. Within host cells, the cytoskeletal vimentin intermediate filament network facilitates viral replication during DENV and ZIKV infection by shrinking and forming a cage-like structure. Our previous work indicated that MEK1/2 inhibitors can induce the dispersion of vimentin, but their potential impact on flavivirus infection remains unclear. Here, we observed that the MEK1/2 signaling pathway is activated in host cells infected with DENV and ZIKV. Treatment with MEK1/2 inhibitors significantly impaired the replication of both viruses. Further mechanistic studies revealed that MEK1/2 inhibitors prevent viral infection by promoting the dispersion of intracellular vimentin network, thereby disrupting the cytoskeletal structure required for viral replication. Our findings not only expand the understanding of vimentin regulatory mechanisms from a cellular biology perspective but also provide a new perspective on MEK1/2 inhibition as a potential anti-DENV and anti-ZIKV strategy.

The functional specificity of tubulin isotypes has been demonstrated by various neurological diseases caused by an increasing number of mutations in tubulin isotypes. TUBA8 is specifically localized in cerebellar Purkinje cells, which exhibit the most elaborate dendritic trees in the central nervous system. However, the role and related molecular mechanism of TUBA8 in regulating neuronal dendritic morphology remain poorly understood. Here, we report that TUBA8 is required for neuronal dendrite development. As the most divergent member in α-tubulin isotypes, the expression of TUBA8 in Purkinje cells starts at P0, plateaus at P10 and sustains into adulthood. Loss of TUBA8 in Purkinje cells induces global dendritic height defects in multiple lobules during development and aging. Meanwhile, TUBA8 deficiency causes age-dependent decreased locomotor activity and anxiety-like behavior. In contrast to TUBA8, TUBA4A, another tubulin isotype highly expressed in Purkinje cells, is not required for dendrite development. Furthermore, the 40th alanine, which differs with any other α-tubulin isotype and cannot be modified by acetylation, methylation or lactylation, mediates the promoting effect of TUBA8 in neuronal dendrite development. This study reveals a specific role of TUBA8 in regulating neuronal dendritic morphology and highlights the importance of 40th amino acid in implementing functions of α-tubulin isotypes.

Amyloid precursor protein (APP), a type I transmembrane protein, is closely related to the pathogenesis of Alzheimer's disease (AD). Amyloid beta (Aβ) is generated by sequential processing of APP in the Golgi apparatus and endosomes, and its toxicity leads to neuron dysfunction and neurodegeneration. APP is selectively shuttled between intracellular membrane compartments and ultimately transported into lysosomes. However, the mechanisms underlying APP sorting signals and lysosomal degradation are largely unclear. In this study, we show that the von Hippel‒Lindau protein (VHL), a subunit of an E3 ligase, recognizes the cytoplasmic domain of APP and mediates its ubiquitination. VHL-mediated ubiquitination facilitates the sorting of membrane APP into intraluminal vesicles of multivesicular bodies (MVBs) and subsequent degradation in lysosomes. Therefore, the loss of VHL accelerates Aβ plaque deposition and memory deficits in AD model mice. Our findings reveal the role of VHL in restricting AD pathogenesis through ubiquitination-dependent MVB sorting and lysosomal degradation of APP.

Organ transplantation is a definitive therapeutic option for patients with end-stage organ dysfunction and failure. Ischaemia-reperfusion (IR) injury is one of the leading causes of low graft utilisation as it significantly increases the risk of primary graft dysfunction and acute rejection following transplantation. This risk is particularly high for organs obtained from donors after circulatory death (DCD) when compared with the donors from brain death (DBD). IR injury exacerbates tissue damage via various mechanisms including the induction of regulated cell death. Regulated cell death and its consequences play critical roles in determining graft survival and function, thereby influencing the overall success of the transplant. Understanding the mechanisms underlying regulated cell death in IR injury is essential for developing therapeutic strategies to minimise tissue damage and improve clinical outcomes in organ transplantation. This review mainly discussed different types of regulated cell death and underlying mechanisms towards preventive cell death strategies in DBD and DCD organ transplantation in preclinical settings.

Tumor-associated fibroblasts (CAFs) regulate tumorigenesis, tumor cell proliferation, and metastasis via secreting related regulatory factors; however, the evidence for CAFs in regulating development of upper tract urothelial carcinoma (UTUC) remains unclear. Here, by utilizing single-cell RNA sequencing (scRNA-seq), single-nucleus RNA sequencing (snRNA-seq), SpaTial enhanced resolution omics-sequencing (Stereo-seq), and UTUC immunofluorescence chip cohort to construct the first comprehensive microenvironmental atlas of CAFs, we investigated the roles of CAFs in UTUC progression. Through hierarchical clustering and the copy number variation (CNV) scores of UTUC epithelial cells, we first classified tumor epithelial cells into high-malignant, medium-malignant, and low-malignant potential categories. We found that the myofibroblastic CAFs1 (myCAFs1) and myCAFs2 subclusters exhibited significant interaction signals with all three types of epithelial cells, among which high-malignant epithelial cells (HMECs) exhibited pronounced communication signals with CAFs, and FN1 and COL1A1 generated by CAFs played critical roles in this process, suggesting that the progression of UTUC may be attributed to the activation of tumor cells by CAFs. Both myCAFs1 and myCAFs2 simultaneously affect bladder urothelial carcinoma (BUC) prognosis, with the risk model showing good consistency across cohorts. The study constructs a multi-omics landscape of UTUC and identify common prognostic markers shared with BUC.

Multiple sclerosis (MS) is an immune-mediated disease in the central nervous system that is characterized by demyelination, axonal degeneration, and progressive neurological disability and is so far incurable. Current medications are predominantly immune-targeted but fail to prevent disease progression due to their inability to actively promote remyelination. Small molecules have been reported to promote myelin regeneration but their therapeutic efficacy is limited by insufficient immune modulation. Thus, the strategies achieving both immunomodulation and active myelin regeneration are highly desired. Here, we investigated a combination therapy (CT) for MS designed to simultaneously modulate immune responses and promote oligodendrocyte precursor cell differentiation and in situ remyelination in an experimental autoimmune encephalomyelitis mouse model. Remarkably, CT suppressed acute inflammatory activity, activated the signaling pathways for myelin development, induced the expression of myelin-related genes, and significantly promoted remyelination and the recovery of motor performance. Furthermore, a reduced immunomodulator dosage or shorter treatment duration with small-molecule drugs achieved comparable symptom reversal. Our findings demonstrate the potential of CT to address complex pathobiology and lay a foundation for developing novel therapeutic strategies for MS.