The FASEB Journal最新文献

Vitiligo is characterized by the depletion of melanocytes due to the activation of CD8⁺ T cells. Taurine-upregulated gene 1 (TUG1), a long noncoding RNA, is involved in melanogenesis. This study aimed to explore the role and mechanism of TUG1 in vitiligo. RT-qPCR and western blot analyses demonstrated decreased TUG1 levels and increased miR-375 levels in patients with vitiligo. MTT and transwell assays indicated that TUG1 upregulation facilitated melanocyte survival and inhibited CD8⁺ T cell migration. Dual luciferase reporter and chromatin immunoprecipitation assays verified that Forkhead box O3 (FOXO3) directly interacted with the TUG1 promoter, leading to the positive regulation of TUG1 expression. In addition, FOXO3 promoted melanocyte survival by enhancing the transcription of TUG1. Luciferase reporter assay and RNA immunoprecipitation assay confirmed that TUG1 upregulated GATA binding protein 3 (GATA3) expression by targeting miR-375. TUG1 facilitated melanocyte survival by regulating the miR-375/GATA3 axis. In vitiligo, melanocyte survival is promoted by the induction of the TUG1-mediated miR-375/GATA3 axis by FOXO3, which offers new therapeutic targets for vitiligo treatment.

The Epstein–Barr virus (EBV) is a ubiquitous gamma-herpesvirus and a class 1 carcinogen that is closely associated with a series of malignant lymphomas and epithelial cell carcinomas. Although these EBV-related cancers may exhibit different features in clinical symptoms and anatomical sites, they all have a characteristic immune-suppressed tumor immune microenvironment (TIME) that is tightly correlated with an abundance of tumor-infiltrating lymphocytes (TILs) that primarily result from the EBV infection. Overwhelming evidence indicates that an upregulation of immune-checkpoint molecules is a powerful strategy employed by the EBV to escape immune surveillance. While previous studies have mainly focused on the therapeutic effects of PD-1 and CTLA-4 blockades in treating EBV-associated tumors, several novel inhibitory receptors (e.g., CD47, LAG-3, TIM-3, VISTA, and DDR1) have recently been identified as potential targets for treating EBV-associated malignancies (EBVaMs). This review retrospectively summarizes the biological mechanisms used for immune checkpoint evasion in EBV-associated tumors. Its purpose is to update our current knowledge concerning the underlying mechanisms by which an immune checkpoint blockade triggers host antitumor immunity against EBVaMs. Additionally, this review may help investigators to more fully understand the correlation between EBV infection and tumor development and subsequently develop novel therapeutic strategies.

Approximately 50% of patients with chronic neuropathic pain experience cognitive impairment, which negatively impacts their quality of life. The cannabinoid type 2 receptor (CB2R) may be involved in hippocampal cognitive processes. However, its role in chronic neuropathic pain-induced cognitive impairment remains elusive. Spared nerve injury (SNI) was used to induce chronic neuropathic pain in rats, while the novel-object recognition test and the Y-maze test were employed to assess cognitive function. Immunofluorescence, western blotting, and stereotaxic hippocampal microinjection were utilized to elucidate the potential mechanisms. We observed a reduction in mechanical pain threshold and cognitive impairment in SNI rats. This was accompanied by a tendency for hippocampal microglia to adopt pro-inflammatory functions. Notably, no changes were detected in CB2R expression. However, downregulation of the endogenous ligands AEA and 2-AG was evident. Hippocampal microinjection of a CB2R agonist mitigated cognitive impairment in SNI rats, which correlated with a tendency for microglia to adopt anti-inflammatory functions. Additionally, SNI-induced activation of the p-ERK/NFκB pathway in the hippocampus. Activation of CB2R reversed this process by upregulating DUSP6 expression in microglia. The effects elicited by CB2R activation could be inhibited through the downregulation of microglial DUSP6 via hippocampal adeno-associated virus (AAV) microinjection. Conversely, overexpression of hippocampal DUSP6 using AAV ameliorated the cognitive deficits observed in SNI rats, which remained unaffected by the administration of a CB2R antagonist. Our findings demonstrate that activation of hippocampal CB2R can mitigate chronic neuropathic pain-induced cognitive impairment through the modulation of the DUSP6/ERK/NFκB pathway.

Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and its dysregulation leads to a variety of human diseases. Although NPRL2, an essential component of the GATOR1 complex, is reported to effectively suppress amino acid-induced mTORC1 activation, the regulation of NPRL2 protein stability is unclear. In this study, we show that chaperon-associated ubiquitin ligase CHIP interacts with NPRL2 and promotes its polyubiquitination and proteasomal degradation. Moreover, HSP70 mediates CHIP-induced ubiquitination and degradation of NPRL2. Consistently, overexpression of HSP70 enhances whereas HSP70 depletion inhibits amino acid-induced mTORC1 activation. Accordingly, knockdown of HSP70 promotes basal autophagic flux, and inhibits cell growth and proliferation. Taken together, these results demonstrated that HSP70 is a novel activator of mTORC1 through mediating CHIP-induced ubiquitination and degradation of NPRL2.

Schizophrenia is a mental disorder characterized by cognitive impairments, specifically deficits in social recognition memory (SRM). Abnormal hippocampal neurogenesis has been implicated in these deficits. Due to the pathogenetic heterogeneity of schizophrenia, studying the hippocampal neurogenesis and SRM in two models with prenatal and postnatal defects could enhance our understanding of the developmental aspects of the biological susceptibility to schizophrenia. Here, we examined SRM and hippocampal neurogenesis in two developmental models of schizophrenia: gestational exposure to methylazoxymethanol acetate (MAM) and postweaning social isolation (SI). Our findings revealed that gestational MAM exposure induced a decay of social memory while postweaning SI led to impaired social memory formation and decay. In both models, we observed a correlation between impaired SRM and reduced number, and abnormal differentiation and less complex morphology of hippocampal neurons. These results indicate that aberrant hippocampal neurogenesis may contribute to the deficits of SRM in both models, and these abnormalities may be a shared underlying pathogenic factor in developmental models of schizophrenia, regardless of prenatal and postnatal pathogenesis.

Uterine carcinosarcoma (UCS) is a rare and highly aggressive gynecological malignancy characterized by poor prognosis. Due to its rarity, UCS remains relatively unexplored, and specific treatment guidelines are scarce. Despite standard treatments, including surgery, adjuvant chemotherapy, and radiotherapy, UCS has a high recurrence rate and poor overall prognosis. The aggressive nature of UCS is attributed to the metaplastic transformation of carcinomatous elements into sarcoma. This “biphasic” neoplasm features a mixture of epithelial and mesenchymal/tumor components, which partially share molecular signatures and exhibit a typical epithelial-to-mesenchymal transition (EMT) gene expression profile. Recent scientific advancements have highlighted the pivotal role of EMT in UCS progression and mortality. This review covers the epidemiology of UCS, theories regarding its origin, and the current state of clinical trials with more emphasis on the role of EMT drivers in UCS progression and scope of targeting these molecules. By shedding light on the molecular mechanisms supporting UCS, particularly emphasizing the importance of EMT, we aim to provide a more comprehensive understanding of the disease to support the development of more effective therapeutic strategies.

The role of long non-coding RNAs in fibroid pathogenesis remains largely unexplored. In a previous study, we found elevated XIST (X-inactive specific transcript) levels in fibroids, which sponged miR-29c and miR-200c, leading to the overexpression of their target genes. This study aimed to assess the therapeutic potential of XIST downregulation in fibroid treatment. Ovariectomized SCID (severe combined immunodeficiency) mice were implanted with fibroid tumors transduced with XIST siRNA or a control via lentivirus. After 1 month, animals were sacrificed and the xenografts were removed for further analysis. XIST knockdown reduced tumor weight by 15% and increased miR-29c and miR-200c expression by 3.9-fold and 2.2-fold, respectively. The mRNA expression of miR-29c targets (COL3A1, TGF-β3, CDK2, SPARC) and miR-200c targets (CDK2, FN1, TDO2), as well as PRL, E2F1, and EZH2, was significantly decreased. Protein abundance of collagen, COL3A1, FN1, CDK2, SPARC, and EZH2 was also reduced. IHC analysis of xenograft sections using the markers of Ki67 for cell proliferation and cleaved caspase 3 for apoptosis showed decreased cell proliferation and no changes in apoptosis in the XIST knockdown xenografts. This analysis also revealed decreased collagen and E2F1 staining nuclei in the XIST knockdown xenografts. These results indicate that downregulation of XIST in fibroids has beneficial therapeutic effects, by reducing tumor growth and the expression of genes involved in cell proliferation, inflammation, and extracellular matrix regulation.

Schüning T, Zeug A, Strienke K, et al. The spinal muscular atrophy gene product regulates actin dynamics. FASEB J. 2024;38:e70055. doi:10.1096/fj.202300183R

The order and assignment of the affiliations to the authors in the published version of the manuscript is incorrect. The incorrect assignment as published is as follows:

“Tobias Schüning1,2 | Andre Zeug3 | Katharina Strienke1,2 | Peter Franz4 |Georgios Tsiavaliaris4 | Niko Hensel2 | Gabriella Viero5 |Evgeni Ponimaskin2 | Peter Claus1,6,7

1SMATHERIA gGmbH—Non-Profit Biomedical Research Institute, Hannover, Germany

2Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

3Institute of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany

4Cellular Biophysics, Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany

5Institute of Biophysics (IBF), CNR Unit at Trento, Trento, Italy

6Center for Systems Neuroscience (ZSN), Hannover, Germany

7Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany”

The correct assignment is as follows:

“Tobias Schüning¹ | Andre Zeug² | Katharina Strienke^1,6 | Peter Franz³ | Georgios Tsiavaliaris³ | Niko Hensel⁴ | Gabriella Viero⁵ | Evgeni Ponimaskin² | Peter Claus^1,6,7

¹SMATHERIA gGmbH—Non-Profit Biomedical Research Institute, Hannover, Germany

²Institute of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany

³Cellular Biophysics, Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany

⁴Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

⁵Institute of Biophysics (IBF), CNR Unit at Trento, Trento, Italy

⁶Center for Systems Neuroscience (ZSN), Hannover, Germany

⁷Institue of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany”

The authors apologize for this error.

Fibroblast growth factor 21 (FGF21) is a promising target for treatment of obesity-associated diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. We evaluated the effects of the bispecific anti-FGF21-β klotho (KLB) agonist antibody bFKB1 in a preclinical model of MASH and atherosclerosis. Low-density lipoprotein receptor knockout (Ldlr−/−).Leiden mice received a high-fat diet for 20 weeks, followed by treatment with an isotype control antibody or bFKB1 for 12 weeks. Effects on plasma risk markers and (histo)pathology of liver, adipose tissue, and heart were evaluated alongside hepatic transcriptomics analysis. bFKB1 lowered body weight (−21%) and adipose tissue mass (−22%) without reducing food intake. The treatment also improved plasma insulin (−80%), cholesterol (−48%), triglycerides (−76%), alanine transaminase (ALT: −79%), and liver weight (−43%). Hepatic steatosis and inflammation were strongly reduced (macrovesicular steatosis −34%; microvesicular steatosis −100%; inflammation −74%) and while the total amount of fibrosis was not affected, bFKB1 did decrease new collagen formation (−49%). Correspondingly, hepatic transcriptomics and pathway analysis revealed the mechanistic background underlying these histological improvements, demonstrating broad inactivation of inflammatory and profibrotic transcriptional programs by bFKB1. In epididymal white adipose tissue, bFKB1 reduced adipocyte size (−16%) and inflammation (−52%) and induced browning, signified by increased uncoupling protein-1 (UCP1) protein expression (8.5-fold increase). In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area (−38%). bFKB1 has strong beneficial metabolic effects associated with a reduction in hepatic steatosis, inflammation, and atherosclerosis. Analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration as well.

Priority 1: critical WHO pathogen Acinetobacter baumannii depends on ATP synthesis and ATP:ADP homeostasis and its bifunctional F₁F_O-ATP synthase. While synthesizing ATP, it regulates ATP cleavage by its inhibitory ε subunit to prevent wasteful ATP consumption. We determined cryo-electron microscopy structures of the ATPase active A. baumannii F₁-αßγε_Δ134–139 mutant in four distinct conformational states, revealing four transition states and structural transformation of the ε's C-terminal domain, forming the switch of an ATP hydrolysis off- and an ATP synthesis on-state based. These alterations go in concert with altered motions and interactions in the catalytic- and rotary subunits of this engine. These A. baumannii interacting sites provide novel pathogen-specific targets for inhibitors, with the aim of ATP depletion and/or ATP synthesis and growth inhibition. Furthermore, the presented diversity to other bacterial F-ATP synthases extends the view of structural elements regulating such a catalyst.