Metastasis-associated protein 1 (MTA1), a master chromatin modifier, has been shown to regulate cancer progression and is widely upregulated in human cancer including, hepatitis B virus-associated hepatocellular carcinomas (HCC). Here we provide evidence that hepatitis B virus transactivator protein HBx stimulates the expression of MTA1 but not MTA2 or MTA3. The underlying mechanism of HBx stimulation of MTA1 involves HBx targeting of transcription factor NF-κB and the recruitment of HBx/p65 complex to the NF-κB -consensus motif on the relaxed MTA1 gene chromatin. We also discovered that MTA1 depletion in HBx-expressing cells severely impairs the ability of HBx to stimulate NF-κB signaling and the expression of target pro-inflammatory molecules. Furthermore the presence of HBx in HBx-infected hepatocellular carcinomas correlated well with increased MTA1 and NF-κB-p65. Collectively, these findings revealed a previously unrecognized integral role of MTA1 in HBx stimulation of NF-κB signaling and consequently, the expression of NF-κB targets gene products with functions in inflammation and tumorigenesis.
The MTA1 coregulator (metastatic tumor antigen 1), a component of the nucleosome remodeling and deacetylase (NuRD) complex, has been intimately linked with human cancer, but its role in inflammatory responses remains unknown. Here, we discovered that MTA1 is a target of inflammation, and stimulation of macrophages with Escherichia coli lipopolysaccharide (LPS) stimulates MTA1 transcription via the NF-B pathway. Unexpectedly, we found that MTA1 depletion in LPS-stimulated macrophages impairs NF-B signaling and expression of inflammatory molecules. MTA1 itself acts as a transcriptional coactivator of inflammatory cytokines in LPS-stimulated macrophages, and in contrast, it acts as a corepressor in resting primary macrophages as its depletion induced cytokine expression. LPS stimulates S-nitrosylation of histone deacetylase 2 (HDAC2) and interferes with its binding to MTA1, which, in turn, resulted in the loss of corepressor behavior of MTA1⅐HDAC complex in activated macrophages. Consequently, the net levels of inflammatory cytokines in LPSstimulated macrophages from MTA1 ؊/؊ mice were high compared with wild-type mice. Accordingly, MTA1 ؊/؊ mice were much more susceptible than control mice to septic shock induced by LPS, revealing that MTA1 protects mice from deregulated host inflammatory response. These findings reveal a previously unrecognized, critical homeostatic role of MTA1, both as a target and as a component of the NF-B circuitry, in the regulation of inflammatory responses.
Nitric oxide has been implicated in the pathogenesis of inflammatory disorders, including hepatitis B virus-associated hepatocellular carcinoma. Transactivator protein HBx, a major regulator of cellular responses of hepatitis B virus, is known to induce the expression of MTA1 (metastasis-associated protein 1) coregulator via NF-B signaling in hepatic cells. However, the underlying mechanism of HBx regulation of the inducible nitric-oxide synthase (iNOS) pathway remains unknown. Here we provide evidence that MTA1 is a positive regulator of iNOS transcription and plays a mechanistic role in HBx stimulation of iNOS expression and activity. We found that the HBx-MTA1 complexisrecruitedontothehumaniNOSpromoterinanNF-Bdependent manner. Pharmacological inhibition of the NF-B signaling prevented the ability of HBx to stimulate the transcription, the expression, and the activity of iNOS; nevertheless, these effects could be substantially rescued by MTA1 dysregulation. We further discovered that HBx-mediated stimulation of MTA1 is paralleled by the suppression of miR-661, a member of the small noncoding RNAs, recently shown to target MTA1. We observed that miR-661 controls of MTA1 expression contributed to the expression and activity of iNOS in HBx-expressing HepG2 cells. Accordingly, depletion of MTA1 by either miR-661 or siRNA in HBx-expressing cells severely impaired the ability of HBx to modulate the endogenous levels of iNOS and nitrite production. Together, these findings reveal an inherent role of MTA1 in HBx regulation of iNOS expression and consequently its function in the liver cancer cells.
Although metastasis tumor antigen 1 (MTA1) contributes to the responsiveness of macrophages to LPS, the underlying mechanism remains unknown. Here, we investigated the role of MTA1 in the regulation of expression and function of MyD88, a proximal component of NF-B signaling. We discovered that MTA1 targets MyD88 and that MyD88 is a NF-B-responsive gene in LPS-stimulated macrophages. We found that MTA1 is required for MyD88-dependent stimulation of NF-B signaling and expression of proinflammatory cytokines such as IL-1, MIP2, and TNF-␣ as MTA1 depletion leads to a substantial reduction in the expression of NF-B target genes. In addition, LPS-mediated stimulation of MyD88 transcription was accompanied by an enhanced recruitment of MTA1, RNA polymerase II, and p65RelA complex to the NF-B consensus sites in the MyD88 promoter. Interestingly, the recruitment of both MTA1 and MyD88 expression is effectively blocked by NF-B inhibitor parthenolide. Selective knockdown of MyD88 by a dominant negative mutant of MyD88 or selective siRNA also impairs the ability of LPS to stimulate the NF-B target genes. These findings reveal an inherent coregulatory role of MTA1 upon the expression of MyD88 and suggest that MTA1 regulation of MyD88 may constitute at least one of the mechanisms by which MTA1 stimulates LPS-induced NF-B signaling in stimulated macrophages. Toll-like receptors (TLRs)2 play a key role in the innate immune system, particularly in the inflammatory response against various microorganisms by recognizing pathogen-associated molecular patterns (1-4). Upon the recognition of pathogen-associated molecular patterns, TLR signaling promptly induces immune responses that signal through adaptor molecules, the myeloid differentiation primary response gene 88 (MyD88), Toll/interleukin (IL)-1 receptor (TIR) domain containing adaptor protein (TIRAP), TIR domain containing adaptor-inducing interferon (IFN)- (TRIF), and TRIF-related adaptor molecules (TRAM), eventually to activate transcriptional factors such as nuclear factor (NF)-B, activator protein 1 (AP-1), and IFN regulatory factors to induce antibacterial and antiviral responses (5, 6). Among the TLRs, TLR4 is the major receptor involved in the detection of Gram-negative bacteria and their associated endotoxins such as lipopolysaccharide (LPS) (7) and signal through MyD88, leading to the subsequent downstream activation of NF-B and mitogen-associated protein kinase (MAPK) signaling pathways (8). These signaling cascades are responsible for induction of proinflammatory cytokines and chemokines (9).LPS activates two signal transduction pathways, i.e. MyD88-dependent and -independent pathways (10 -13). The MyD88-dependent pathway activates NF-B, which results in the production of proinflammatory cytokines, such as IL-1, IL-6, and TNF-␣ and ultimately leads to the activation and accumulation of monocytes (14). In contrast, the MyD88-independent pathway activates interferon regulatory factor-3, resulting in the expression of IFN- and IFN-inducible genes. MyD88-dependent TL...
Anti-N-methyl-d-aspartate receptor (anti-NMDA-R) encephalitis is an autoimmune disorder that was first described by Dr Vitaliani in 2005. In 2007, Dalmau et al. found anti-NMDA-R antibody expressed both in the hippocampus and prefrontal nerve cell membrane, finally proposing the diagnosis of autoimmune anti-NMDA-R encephalitis. Most of the patients are female (91%), with ages ranging from 4 to 76 years. The average age is 23 years, a birth peak age, although anti-NMDA-R encephalitis is rare during pregnancy. The disorder is characterized by prominent psychosis, dyskinesias, seizures, autonomic disturbance, and central hypoventilation. We report a 24-year-old woman hospitalized at 28 gestational weeks with acute-onset psychosis. Over the course of 3 weeks, her mental status worsened until she fell into a coma. Both serum and cerebrospinal fluid anti-NMDA-R antibodies were found to be positive. At cesarean section, a healthy baby boy was born and a wedge-shaped bilateral ovarian resection was performed. Treatment with corticosteroids, intravenous immunoglobulin, and plasmapheresis can lead to improved outcomes for both mother and baby.
BackgroundExposure to dichlorvos (DDVP), an organophosphorus pesticide, is known to result in neurotoxicity as well as other metabolic perturbations. However, the molecular causes of DDVP toxicity are poorly understood, especially in cells other than neurons and muscle cells. To obtain a better understanding of the process of non-neuronal DDVP toxicity, we exposed zebrafish to different concentrations of DDVP, and investigated the resulting changes in liver histology and gene transcription.ResultsFunctional enrichment analysis of genes affected by DDVP exposure identified a number of processes involved in energy utilization and stress response in the liver. The abundance of transcripts for proteins involved in glucose metabolism was profoundly affected, suggesting that carbon flux might be diverted toward the pentose phosphate pathway to compensate for an elevated demand for energy and reducing equivalents for detoxification. Strikingly, many transcripts for molecules involved in β-oxidation and fatty acid synthesis were down-regulated. We found increases in message levels for molecules involved in reactive oxygen species responses as well as ubiquitination, proteasomal degradation, and autophagy.To ensure that the effects of DDVP on energy metabolism were not simply a consequence of poor feeding because of neuromuscular impairment, we fasted fish for 29 or 50 h and analyzed liver gene expression in them. The patterns of gene expression for energy metabolism in fasted and DDVP-exposed fish were markedly different.ConclusionWe observed coordinated changes in the expression of a large number of genes involved in energy metabolism and responses to oxidative stress. These results argue that an appreciable part of the effect of DDVP is on energy metabolism and is regulated at the message level. Although we observed some evidence of neuromuscular impairment in exposed fish that may have resulted in reduced feeding, the alterations in gene expression in exposed fish cannot readily be explained by nutrient deprivation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1941-2) contains supplementary material, which is available to authorized users.
The toxicity of dichlorvos (DDVP), an organophosphate (OP) pesticide, classically results from modification of the serine in the active sites of cholinesterases. However, DDVP also forms adducts on unrelated targets such as transferrin and albumin, suggesting that DDVP could cause perturbations in cellular processes by modifying noncholinesterase targets. Here we identify novel DDVP-modified targets in lysed human hepatocyte-like cells (HepaRG) using a direct liquid chromatography-mass spectrometry (LC-MS) assay of cell lysates incubated with DDVP or using a competitive pull-down experiments with a biotin-linked organophosphorus compound (10-fluoroethoxyphosphinyl-N-biotinamidopentyldecanamide; FP-biotin), which competes with DDVP for similar binding sites. We show that DDVP forms adducts to several proteins important for the cellular metabolic pathways and differentiation, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and actin. We validated the results using purified proteins and enzymatic assays. The study not only identified novel DDVP-modified targets but also suggested that the modification directly inhibits the enzymes. The current approach provides information for future hypothesis-based studies to understand the underlying mechanism of toxicity of DDVP in non-neuronal tissues. The MS data have been deposited to the ProteomeXchange with identifier PXD001107.
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