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Project description:BACKGROUND:The central nervous system (CNS) is vulnerable to viral infection, yet few host factors in the CNS are known to defend against invasion by neurotropic viruses. Long noncoding RNAs (lncRNAs) have been revealed to play critical roles in a wide variety of biological processes and are highly abundant in the mammalian brain, but their roles in defending against invasion of pathogens into the CNS remain unclear. RESULTS:We report here that multiple neurotropic viruses, including rabies virus, vesicular stomatitis virus, Semliki Forest virus, and herpes simplex virus 1, elicit the neuronal expression of a host-encoded lncRNA EDAL. EDAL inhibits the replication of these neurotropic viruses in neuronal cells and rabies virus infection in mouse brains. EDAL binds to the conserved histone methyltransferase enhancer of zest homolog 2 (EZH2) and specifically causes EZH2 degradation via lysosomes, reducing the cellular H3K27me3 level. The antiviral function of EDAL resides in a 56-nt antiviral substructure through which its 18-nt helix-loop intimately contacts multiple EZH2 sites surrounding T309, a known O-GlcNAcylation site. EDAL positively regulates the transcription of Pcp4l1 encoding a 10-kDa peptide, which inhibits the replication of multiple neurotropic viruses. CONCLUSIONS:Our findings show that a neuronal lncRNA can exert an effective antiviral function via blocking a specific O-GlcNAcylation that determines EZH2 lysosomal degradation, rather than the traditional interferon-dependent pathway.
| S-EPMC7465408 | biostudies-literature
Project description:A novel antiviral lncRNA, EDAL, shields a T309 O-GlcNAcylation site to promote EZH2 lysosomal degradation
| PRJNA419742 | ENA
Project description:O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) is the only known enzyme that catalyzes the O-GlcNAcylation of proteins at the Ser or Thr side chain hydroxyl group. OGT participates in transcriptional and epigenetic regulation, and dysregulation of OGT has been implicated in diseases such as cancer. However, the underlying mechanism is largely unknown. Here we show that OGT is required for the trimethylation of histone 3 at K27 to form the product H3K27me3, a process catalyzed by the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in the polycomb repressive complex 2 (PRC2). H3K27me3 is one of the most important histone modifications to mark the transcriptionally silenced chromatin. We found that the level of H3K27me3, but not other H3 methylation products, was greatly reduced upon OGT depletion. OGT knockdown specifically down-regulated the protein stability of EZH2, without altering the levels of H3K27 demethylases UTX and JMJD3, and disrupted the integrity of the PRC2 complex. Furthermore, the interaction of OGT and EZH2/PRC2 was detected by coimmunoprecipitation and cosedimentation experiments. Importantly, we identified that serine 75 is the site for EZH2 O-GlcNAcylation, and the EZH2 mutant S75A exhibited reduction in stability. Finally, microarray and ChIP analysis have characterized a specific subset of potential tumor suppressor genes subject to repression via the OGT-EZH2 axis. Together these results indicate that OGT-mediated O-GlcNAcylation at S75 stabilizes EZH2 and hence facilitates the formation of H3K27me3. The study not only uncovers a functional posttranslational modification of EZH2 but also reveals a unique epigenetic role of OGT in regulating histone methylation.
| S-EPMC3910655 | biostudies-literature
Project description:The complex bacterial populations that constitute the gut microbiota can harbor antibiotic resistance genes (ARGs), including those encoding β-lactamase enzymes (BLA), which degrade commonly prescribed antibiotics such as ampicillin. The prevalence of such genes in commensal bacteria has been increased in recent years by the wide use of antibiotics in human populations and in livestock. While transfer of ARGs between bacterial species has well-established dramatic public health implications, these genes can also function in trans within bacterial consortia, where antibiotic-resistant bacteria can provide antibiotic-sensitive neighbors with leaky protection from drugs, as shown both in vitro and in vivo, in models of lung and subcutaneous coinfection. However, whether the expression of ARGs by harmless commensal bacterial species can destroy antibiotics in the intestinal lumen and shield antibiotic-sensitive pathogens is unknown. To address this question, we colonized germfree or wild-type mice with a model intestinal commensal strain of Escherichia coli that produces either functional or defective BLA. Mice were subsequently infected with Listeria monocytogenes or Clostridioides difficile, followed by treatment with oral ampicillin. The production of functional BLA by commensal E. coli markedly reduced clearance of these pathogens and enhanced systemic dissemination during ampicillin treatment. Pathogen resistance was independent of ARG acquisition via horizontal gene transfer but instead relied on antibiotic degradation in the intestinal lumen by BLA. We conclude that commensal bacteria that have acquired ARGs can mediate shielding of pathogens from the bactericidal effects of antibiotics.
| S-EPMC7093146 | biostudies-literature
Project description:T cell immunoglobulin and mucin domain (TIM) proteins are cell-surface signaling receptors in T cells and scavenger receptors in antigen-presenting cells and kidney tubular epithelia. Here, we demonstrated a function for TIM proteins in mediating the degradation of NUR77, a nuclear receptor implicated in apoptosis and cell survival. TIM proteins interacted with and mediated the lysosomal degradation of NUR77 in a phosphoinositide 3-kinase-dependent pathway. We also showed dynamic cycling of TIM-1 to and from the cell surface through clathrin-dependent constitutive endocytosis. Blocking this process or mutating the phosphatidylserine-binding pocket in TIM-1 abrogated TIM-1-mediated degradation of NUR77. In an in vitro model of kidney injury, silencing TIM-1 increased NUR77 abundance and decreased epithelial cell survival. These results show that TIM proteins may affect immune cell function and the response of the kidney to injury.
| S-EPMC3767312 | biostudies-literature
Project description:Here, we demonstrate that virus-infected macrophages display decreased expression of serine synthesis pathway (SSP) enzymes. Suppressing the SSP key enzyme phosphoglycerate dehydrogenase (PHGDH) by genetic approaches enhanced IFN-b-mediated antiviral innate immunity in vitro and in vivo. To further explore its mechanism, we used high-throughput sequencing technology (RNA-seq) to assess gene expression in PHGDH-deficiency BMDMs and RAW264.7 macrophages.
2021-01-29 | GSE165684 | GEO
Project description:TGF-β signaling plays a pivotal role in promoting tumor cell migration and cancer metastasis. ΔNp63α and TAp63α are two major isoforms of p53-related p63 protein. Our recent study has shown that TGF-β1 promotes ΔNp63α protein degradation to facilitate cancer metastasis. However, whether TAp63α is involved in TGF-β1-induced cancer metastasis remains unclear. In this study, we show that, in human pancreatic cancer MIA PaCa-2 cells harboring p53-R248W allele, TGF-β1 can significantly inhibit TAp63α protein stability in a Smad pathway-independent manner. Lysosome inhibitor, chloroquine, but not proteasome inhibitor MG132, can rescue TGF-β1-induced downregulation of TAp63α protein. In addition, we show that either TGF-β1 treatment or silencing of TAp63α can dramatically increase migration of MIA PaCa-2 cells. Importantly, the restored expression of TAp63α can effectively block TGF-β1-induced migration of MIA PaCa-2 cells. Mechanistically, we show that TGF-β1 promotes TAp63α protein degradation, leading to upregulation of p53-R248W protein expression, and consequently resulting in elevated MIA PaCa-2 cell migration. Together, this study indicates that lysosomal degradation is an important way for regulating TAp63α protein fate and highlights that TGF-β1-TAp63α-mutant p53 axis is critically important in pancreatic cancer metastasis.
| S-EPMC8301043 | biostudies-literature
Project description:EZH2 (the Enhancer of Zeste Homolog 2), as a key epigenetic regulator and EMT inducer, participates in a variety of cancer metastasis. EZH2 stability is regulated by several types of post-translational modifications (PTMs).The long non-coding RNAs (lncRNA) have been implicated to have critical roles in multiple carcinogenesis through a wide range of mechanisms, including modulating the stability of proteins. To date, whether the stability of EZH2 protein is regulated by lncRNAs remains unexplored. Here we report the discovery of ANCR modulating the stability of EZH2, and hence in the invasion and metastasis of breast cancer cells. We determined that ANCR potentiated the CDK1-EZH2 interaction, which then increased the intensity of phosphorylation at Thr-345 and Thr-487 sites of EZH2, facilitating EZH2 ubiquitination and hence its degradation. Moreover, we also uncover ANCR is an important player in breast cancer progression and metastasis mainly through decreasing EZH2 stability. More specifically, we initially found that ANCR level was lower in breast cancer tissues and breast cancer cell lines, in contrast to their normal counterparts. We then demonstrated that knockdown of ANCR induced an EMT program and promoted cell migration and invasion in MCF10A (epithelial cells), whereas ectopic expression of ANCR repressed breast cancer cells migration and invasion. Furthermore, we validated in a nude mouse model that overexpression of ANCR in highly malignant and invasive MDA-MB-231 breast cancer cells significantly reduced the ability of the cells to form tumors and prevented the lung metastasis in vivo. Based on these data, our findings define a new mechanism underlying modulation of EZH2 stability by linking ANCR interaction with EZH2 to promote its phosphorylation that facilitates EZH2 degradation and suppresses breast cancer progression.
| S-EPMC5260507 | biostudies-literature
Project description:The RNA binding protein TRA2A, a member of the transformer 2 homolog family, plays a crucial role in the alternative splicing of pre-mRNA. However, it remains unclear whether TRA2A is involved in non-coding RNA regulation and, if so, what are the functional consequences. By analyzing expression profiling data, we found that TRA2A is highly expressed in esophageal cancer and is associated with disease-free survival and overall survival time. Subsequent gain- and loss-of-function studies demonstrated that TRA2A promotes proliferation and migration of esophageal squamous cell carcinoma and adenocarcinoma cells. RNA immunoprecipitation and RNA pull-down assay indicated that TRA2A can directly bind specific sites on MALAT1 in cells. In addition, ectopic expression or depletion of TRA2A leads to MALAT expression changes accordingly, thus modulates EZH2/β-catenin pathway. Together, these findings elucidated that TRA2A triggers carcinogenesis via MALAT1 mediated EZH2/β-catenin axis in esophageal cancer cells.
| S-EPMC8247389 | biostudies-literature
Project description:PTEN is a crucial tumor suppressor and loss of PTEN protein is involved in various cancers. However, the detailed molecular mechanisms of PTEN loss in cancers remain elusive, especially the involvement of lncRNAs. Here, lncRNA RP11-295G20.2 is found to be significantly upregulated in hepatocellular carcinoma (HCC) and promotes the growth of liver cancer cells both in vitro and in vivo. Furthermore, RP11-295G20.2 inhibits autophagy in liver cancer cells. Interestingly, RP11-295G20.2 directly binds to the PTEN protein and leads to its degradation. RP11-295G20.2 expression is inversely correlated with PTEN protein expression in 82 TCGA/TCPA-LIHC samples. Surprisingly, RP11-295G20.2-induced PTEN degradation occurs through the lysosomal pathway instead of the proteasome pathway. RP11-295G20.2 binds to the N terminus of PTEN and facilitates the interaction of p62 with PTEN. Thus, PTEN is translocated into lysosomes and degraded. RP11-295G20.2 also influences AKT phosphorylation and forkhead box O 3a (FOXO3a) translocation into the nucleus, in turn regulating the transcription of autophagy-related genes. Collectively, RP11-295G20.2 directly binds to PTEN and enables its lysosomal degradation. This newly identified RP11-295G20.2/PTEN axis reveals an unexplored molecular mechanism regarding PTEN loss in liver cancer and might provide new therapeutic benefits for liver cancer patients.
| S-EPMC8668967 | biostudies-literature