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PubMed2005

Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis.

In inflammatory arthridities such as rheumatoid arthritis, cognate lymphocytes have long been considered instigators of autoimmunity, but accumulating evidence indicates that innate immune cells such as neutrophils and mast cells are responsible for a vast majority of acute and ongoing inflammation; however, the molecular mechanisms that govern them remain largely unknown. Here we show that such inflammation requires the forkhead transcription factor Foxo3a: Foxo3a-deficient mice are resistant to two models of neutrophilic inflammation, immune complex-mediated inflammatory arthritis and thioglycollate-induced peritonitis. This reflects a need for Foxo3a to maintain neutrophil vitality during inflammation by suppressing Fas ligand; because Foxo3a can bind and suppress the Fasl promoter, Foxo3a-deficient neutrophils upregulate Fas ligand and undergo apoptosis in response to TNF-alpha and IL-1, and Fas ligand blockade renders Foxo3a-deficient mice susceptible to both arthritis and peritonitis. Thus, Foxo3a ensures neutrophil survival during inflammation, identifying Foxo3a as therapeutic target in inflammation.

Animals↗

PubMed2003

Natural antibodies and complement are endogenous adjuvants for vaccine-induced CD8+ T-cell responses.

CD8(+) T cells are essential for long-term, vaccine-induced resistance against intracellular pathogens. Here we show that natural antibodies, acting in concert with complement, are endogenous adjuvants for the generation of protective CD8(+) T cells after vaccination against visceral leishmaniasis. IL-4 was crucial for the priming of vaccine-specific CD8(+) T cells, and we defined the primary source of IL-4 as a CD11b(+)CD11c(lo) phagocyte. IL-4 secretion was not observed in antibody-deficient mice and could be reconstituted with serum from normal, but not Btk immune-deficient, mice. Similarly, no IL-4 response or CD8(+) T-cell priming was seen in C1qa(-/-) mice. These results identify a new pathway by which immune complex-mediated complement activation can regulate T-cell-mediated immunity. We propose that this function of natural antibodies could be exploited when developing new vaccines for infectious diseases.

Adjuvants, Immunologic↗

PubMed2003

PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis.

Phosphoinositide 3 kinase enhancer (PIKE) is a recently identified nuclear GTPase that activates nuclear phosphoinositide 3-kinase (PI3 kinase). We have identified, cloned and characterized a new form of PIKE, designated PIKE-L, which, unlike the nuclear PIKE-S, localizes to both the cytoplasm and the nucleus. We demonstrate physiologic binding of PIKE-L to Homer, an adaptor protein known to link metabotropic glutamate receptors to multiple intracellular targets including the inositol 1,4,5-trisphosphate receptor (IP3R). We show that activation of group I metabotropic glutamate receptors (mGluRIs) enhances formation of an mGluRI-Homer-PIKE-L complex, leading to activation of PI3 kinase activity and prevention of neuronal apoptosis. Our findings indicate that this complex mediates the well-known ability of agonists of mGluRI to prevent neuronal apoptosis.

Adenoviridae↗

PubMed2005

G proteins in development.

The focus of developmental biologists has expanded from the analysis of gene expression to include the analysis of cell signalling. Heterotrimeric G proteins (G proteins) mediate signalling from a superfamily of heptahelical receptors (G-protein-coupled receptors) to a smaller number of effector units that include adenylyl cyclases, phospholipase C and various ion channels. The convergence of developmental biology with cell signalling has now revealed overlaps in which G proteins mediate complex pathways in embryonic development.

Animals↗

PubMed2026

Model-driven analysis reveals oxidative stress adaptation enabling efficient energy utilization in a Crabtree-negative Saccharomyces cerevisiae.

Although abolishing the Crabtree effect in Saccharomyces cerevisiae through a pyruvate dehydrogenase bypass eliminates carbon loss through ethanol overflow metabolism, it compromises growth rates. While the Crabtree effect has been a valuable natural adaptation, it is energetically inferior to respiration and is generally undesirable in cell factories engineered to produce assimilatory compounds. Restoring growth efficiency in Crabtree-negative strains remains a central challenge. Through adaptive laboratory evolution of the engineered strain (sZJD23) and subsequent reverse engineering, a variant (sZJD28) with markedly improved growth was identified. This improvement is driven primarily by a mutation in MED2 (encoding a Mediator complex subunit) and, to a lesser extent, a mutation in GPD1 (encoding glycerol-3-phosphate dehydrogenase). By integrating quantitative proteomics with enzyme-constrained genome-scale modelling, we demonstrate that these mutations jointly enable a more efficient mode of oxidative stress adaptation and energy utilization. The GPD1 mutation suppresses a protein-costly, suboptimal NAD⁺-recycling strategy reliant on glycerol synthesis, while the MED2 mutation reshapes the oxidative stress response towards peroxisomal detoxification. Collectively, these adjustments optimize metabolic flux distribution and reduce protein costs in energy metabolism, thereby increasing ATP availability. Our findings reveal how coordinated mutations in regulatory and metabolic genes restore growth fitness in engineered Crabtree-negative yeast.

Saccharomyces cerevisiae↗

PubMed2025

Compensatory evolution to DNA replication stress is robust to nutrient availability.

Evolutionary repair refers to the compensatory evolution that follows perturbations in cellular processes. While evolutionary trajectories are often reproducible, other studies suggest they are shaped by genotype-by-environment (GxE) interactions. Here, we test the predictability of evolutionary repair in response to DNA replication stress-a severe perturbation impairing the conserved mechanisms of DNA synthesis, resulting in genetic instability. We conducted high-throughput experimental evolution on Saccharomyces cerevisiae experiencing constitutive replication stress, grown under different glucose availability. We found that glucose levels impact the physiology and adaptation rate of replication stress mutants. However, the genetics of adaptation show remarkable robustness across environments. Recurrent mutations collectively recapitulated the fitness of evolved lines and are advantageous across macronutrient availability. We also identified a novel role of the mediator complex of RNA polymerase II in adaptation to replicative stress. Our results highlight the robustness and predictability of evolutionary repair mechanisms to DNA replication stress and provide new insights into the evolutionary aspects of genome stability, with potential implications for understanding cancer development.

DNA Replication↗

PubMed2005

The DNA mismatch repair gene hMSH2 is a potent coactivator of oestrogen receptor alpha.

The DNA mismatch repair gene is a key regulator in the elimination of base-base mismatches and insertion/deletion loops (IDLs). Human MutS homologue 2 (hMSH2), originally identified as a human homologue of the bacterial MutS, is a tumour suppressor gene frequently mutated in hereditary non-polyposis colorectal cancer. Hereditary non-polyposis colorectal cancer is characterised by the early onset of colorectal cancer and the development of extracolonic cancers such as endometrial, ovarian, and urological cancers. Oestrogen receptor (ER) alpha and beta are members of a nuclear receptor (NR) superfamily. Ligand-dependent transcription of ER is regulated by the p160 steroid receptor coactivator family, the thyroid hormone receptor-associated proteins/the vitamin D receptor-interacting proteins (TRAP/DRIP) mediator complex, and the TATA box-binding protein (TBP)-free TBP associated factor complex (TFTC) type histone acetyltransferase complex. Here, we report the interaction between ER alpha/beta and hMSH2. Immunoprecipitation and glutathione-S-transferase pull-down assay revealed that ER alpha and hMSH2 interacted in a ligand-dependent manner, whereas ER beta and hMSH2 interacted in a ligand-independent manner. Oestrogen receptor alpha/beta bound to hMSH2 through the hMSH3/hMSH6 interaction domain of hMSH2. In a transient expression assay, hMSH2 potentiated the transactivation function of liganded ER alpha, but not that of ER beta. These results suggest that hMSH2 may play an important role as a putative coactivator in ER alpha dependent gene expression.

Base Pair Mismatch↗

PubMed2004

Characterization of rtSH3p13 gene encoding a development protein involved in vesicular traffic in spermiogenesis.

A cDNA, designated as rtSH3p13, was isolated from a rat testis cDNA library. It consists of 1463 bp nuclear acids, which encodes a protein of 312 amino acids and was assigned the GenBank accession number AF227439. The deduced rtSH3p13 protein is a truncated isoform of SH3p13 as a result of mRNA alternative splicing. It is mainly expressed in the rat testis, detected in spermatids at the steps 8-19 of spermiogenesis, and found around the acrosome. During postnatal development, rtSH3p13 appears on day 18 and reaches maximum on day 60. Further experimental results suggested that rtSH3p13 forms a complex with activated epidermal growth factor receptor (EGFR) and interacts with synaptojanin I. Surprisingly, similar to SH3 domain, the V region of rtSH3p13 also inhibits endocytosis in CHO cells. Our results reveal a link between an rtSH3p13-synaptojanin-clathrin complex-mediated formation of pits and the process of spermiogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Histone H3 phosphorylation can promote TBP recruitment through distinct promoter-specific mechanisms.

Histone phosphorylation influences transcription, chromosome condensation, DNA repair and apoptosis. Previously, we showed that histone H3 Ser10 phosphorylation (pSer10) by the yeast Snf1 kinase regulates INO1 gene activation in part via Gcn5/SAGA complex-mediated Lys14 acetylation (acLys14). How such chromatin modification patterns develop is largely unexplored. Here we examine the mechanisms surrounding pSer10 at INO1, and at GAL1, which herein is identified as a new regulatory target of Snf1/pSer10. Snf1 behaves as a classic coactivator in its recruitment by DNA-bound activators, and in its role in modifying histones and recruiting TATA-binding protein (TBP). However, one important difference in Snf1 function in vivo at these promoters is that SAGA recruitment at INO1 requires histone phosphorylation via Snf1, whereas at GAL1, SAGA recruitment is independent of histone phosphorylation. In addition, the GAL1 activator physically interacts with both Snf1 and SAGA, whereas the INO1 activator interacts only with Snf1. Thus, at INO1, pSer10's role in recruiting SAGA may substitute for recruitment by DNA-bound activator. Our results emphasize that histone modifications share general functions between promoters, but also acquire distinct roles tailored for promoter-specific requirements.

Biological Transport, Active↗

PubMed1999

PEGylated DNA/transferrin-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery.

We investigated the in vitro and in vivo properties of DNA/transferrin-polyethylenimine (800 kDa) complexes before and after covalent coupling of poly(ethylene glycol) (PEG). Upon incubation with plasma, the positively charged non-PEGylated DNA complexes form aggregates. Plasma proteins such as IgM, fibrinogen, fibronectin and complement C3 were found to bind to non-PEGylated DNA complexes. At DNA concentrations relevant for in vivo gene delivery a strong aggregation of erythrocytes was also observed. PEGylation of the complexes strongly reduces plasma protein binding and erythrocyte aggregation. Furthermore, PEGylated complex size was stabilized and had a reduced surface charge. Prolonged circulation in the blood of the PEGylated complexes was also observed when injected intravenously. In tumor bearing mice, application of non-PEGylated complexes through the tail vein resulted in reporter gene expression in tail and lung, but severe toxicity was observed in some mice. In contrast, PEGylated complexes mediated reporter gene transfer to the tumor without significant toxicity.

Animals↗

PubMed2003

Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein.

While PDZ domain-containing proteins represent cellular targets for several different viral oncoproteins, including human papillomavirus E6, human T-cell leukemia virus type 1 Tax, and human adenovirus E4-ORF1, the functional consequences for such interactions have not been elucidated. Here we report that, at the plasma membrane of cells, the adenovirus E4-ORF1 oncoprotein selectively and potently stimulates phosphatidylinositol 3-kinase (PI3K), triggering a downstream cascade of events that includes activation of both protein kinase B and p70S6-kinase. This activity of E4-ORF1 could be abrogated by overexpression of its PDZ-protein targets or by disruption of its PDZ domain-binding motif, which was shown to mediate complex formation between E4-ORF1 and PDZ proteins at the plasma membrane of cells. Furthermore, E4-ORF1 mutants unable to activate the PI3K pathway failed to transform cells in culture or to promote tumors in animals, and drugs that block either PI3K or p70S6-kinase inhibited E4-ORF1-induced transformation of cells. From these results, we propose that the transforming and tumorigenic potentials of the adenovirus E4-ORF1 oncoprotein depend on its capacity to activate PI3K through a novel PDZ protein-dependent mechanism of action.

Adenovirus E4 Proteins↗

PubMed1990

Glycosaminoglycans inhibit formation of the 140 kDa insulin-like growth factor-binding protein complex.

The 140 kDa insulin-like growth factor (IGF)-binding protein complex in human serum consists of three subunits: an acid-labile, non-IGF-binding glycoprotein (alpha-subunit), an IGF-binding glycoprotein known as BP-53 or IGFBP-3 (beta-subunit), and IGF-I or IGF-II (gamma-subunit). This study investigates the regulation, by salt and glycosaminoglycans, of ternary (alpha-beta-gamma) complex formation, measured by incubating radioiodinated alpha-subunit with a mixture of IGF-I and IGFBP-3 and precipitating bound radioactivity with an anti-IGFBP-3 antiserum. Increasing NaCl concentrations progressively decreased ternary complex formation without any effect on binary (beta-gamma) complex formation. In 0.15 M-NaCl, the association constant for the ternary complex was 0.318 +/- 0.092 nM-1, 100-fold lower than that for the binary complex. Glycosaminoglycans also inhibited ternary complex formation without affecting the binary complex. Heparin [50% inhibition at 0.27 +/- 0.08 units/ml (1.5 +/- 0.4 micrograms/ml)] was more potent than heparan sulphate (50% inhibition at 15 +/- 7 micrograms/ml), with chondroitin sulphate even less potent. The inhibition by heparin was due principally to a decrease in binding affinity, from 0.604 +/- 0.125 to 0.151 +/- 0.024 nM-1 in the presence of 0.25 units of heparin/ml, with a slight decrease in the number of apparent binding sites from 1.05 +/- 0.08 to 0.85 +/- 0.15 mol of alpha-subunit bound/mol of beta-subunit. Since the ternary IGF-binding protein complex cannot cross the capillary barrier, it is proposed that a decrease in the affinity of the complex, mediated by circulating or cell-associated glycosaminoglycans, may be important in the passage of IGFs and IGFBP-3 to the tissues.

Binding, Competitive↗

PubMed1999

Erythema elevatum diutinum and HIV infection: a report of five cases.

Erythema elevatum diutinum (EED) is emerging as a specific HIV-associated dermatosis, 11 cases having so far been reported in the medical literature and five patients with the disease having been seen by us during the last 4 years. As the disease is poorly known, it is easily confused with Kaposi's sarcoma or bacillary angiomatosis, but the histopathological features are diagnostic. EED is considered to be an immune complex-mediated vasculitis. A streptococcal infection seemed to be the trigger factor in four of our patients. Partial control of the cutaneous lesions was achieved by the use of antibiotics.

AIDS-Related Opportunistic Infections↗

PubMed2000

Induction of microthrombotic thrombocytopenia in normal mice by transferring a platelet-reactive, monoclonal anti-gp70 autoantibody established from MRL/lpr mice: an autoimmune model of thrombotic thrombocytopenic purpura.

MRL/MpJ-lpr/lpr (MRL/lpr) mice spontaneously develop immune complex-mediated glomerulonephritis and thrombocytopenia. Although the presence of cross-reactive anti-phospholipid antibodies in sera of MRL/lpr mice has been demonstrated, possible relationships between detected autoantibodies and the development of thrombocytopenia have not been elucidated. Recent genetic analyses in a few different strains of lupus-prone mice have pointed out a close correlation between autoantibodies reactive with endogenous retroviral env gene product, gp70, and the development and severity of glomerulonephritis. In the process of establishing possibly nephritogenic anti-gp70 autoantibody-producing hybridoma cells from MRL/lpr mice, we identified an IgG2a-producing anti-gp70 hybridoma clone that induced microvascular intraluminal platelet aggregation, thrombocytopenia, and amenia upon transplantation into syngeneic non-autoimmune mice. This and two other anti-gp70 antibodies bound onto the surface of mouse platelets, and purified IgG2a of the anti-gp70 autoantibody induced glomerular lesions with characteristics of thrombotic thrombocytopenic purpura when injected into non-autoimmune mice. The pathogenic anti-gp70 autoantibody specifically precipitated a platelet protein with an approximate relative molecular mass of 40 000.

Animals↗

PubMed1998

Hepatitis C virus infection in non-Hodgkin's lymphoma.

Hepatitis C virus (HCV) infection is associated with immune-complex mediated disorders, including Type II mixed cryoglobulinaemia. Mixed cryoglobulinaemia is itself a low-grade B-cell lymphoproliferative disorder which may progress to non-Hodgkin's lymphoma (NHL). Studies from Europe and Asia have found a prevalence of hepatitis C virus infection in non-Hodgkin's lymphoma patients as high as 34%. Other viral infections are also associated with non-Hodgkin's lymphoma. We speculated that non-Hodgkin's lymphoma patients in the midwestern USA would have an increased prevalence of hepatitis C infection. We tested 73 patients with NHL and 20 controls with Hodgkin's disease for anti-HCV antibodies by EIA-2. Only 1/73 patients and no control subject was positive for anti-HCV. The anti-HCV positive patient had no identifiable risk factors for hepatitis C, and ALT was persistently normal. HCV-RNA testing by RT-PCR was negative. Thus, none of 73 non-Hodgkin's lymphoma patients could be confirmed to have hepatitis C infection. In a second part of the study, of 438 patients with HCV infection followed an average of 28.1 months, only one patient developed non-Hodgkin's lymphoma. We conclude that in our population, non-Hodgkin's lymphoma is not associated with hepatitis C virus infection. Based on these results and review of the literature, there are marked regional differences in the prevalence of hepatitis C infection in Non-Hodgkin's lymphoma.

Adult↗

PubMed1997

Myelodysplastic syndrome with vasculitic manifestations.

Vasculitis in patients with the myelodysplastic syndrome (MDS) is a rare phenomenon. We describe a patient who presented with necrotic lesions of his toes, which proved to be the result of immune complex mediated vasculitis. This unusual combination of vasculitis and MDS prompted us to review the literature. Forty-four cases of vasculitis in association with MDS were found. The pathogenesis of the vasculitis in MDS remains speculative, although several reports suggest an immunological mechanism. The temporal relationship could not be determined in 20 (45%) of reported cases. The prognosis of these patients appears to be worse than in patients with MDS without vasculitis. Steroids were used in 41 (93%) of the reported cases. Our patient did not receive any drug therapy, nevertheless his necrotic lesions improved within a few weeks.

Aged↗

PubMed1997

Renal disease in lymphatic filariasis: evidence for tubular and glomerular disorders at various stages of the infection.

Brugia malayi-infected patients, endemic normals with high levels of specific antibodies and European controls were investigated for kidney disorders by noninvasive techniques. Groups of patients with filarial infections included asymptomatic, microfilaraemic cases (group 1), patients with filarial fever (group 2) and with obstructive filariasis (group 3). Several patients underwent a treatment course with diethylcarbamazine (DEC) when blood and urine samples were collected. Urine samples were investigated for proteinuria and analysed by SDS-PAGE to discriminate between proteinurias caused by tubular and glomerular disorders. In addition, urine levels of alpha-1 microglobulin, of the brush border antigen gp400 and of N-acetyl-beta-glucosaminidase (NAG) activity were determined as indicators of tubular disorders, the albumin content of the urines served as indicator of glomerular alterations. IgG rheuma factors were also determined in the serum as possible reasons for glomerulonephritis. Neither in the endemic normals nor in the European controls there was evidence for kidney disorders. Infected patients had significantly increased proteinuria compared to controls. There were no significant differences between the 3 groups of infected persons, although the mean protein levels were highest in cases with chronic disease and lowest in asymptomatic patients. Quantitative urine analyses and results of accompanying tests suggest predominantly tubular but generally relatively weak disorders in asymptomatic infections; abundant involvement of the kidney which involves both compartments of the organ in the course of filarial fever; and partly severe and probably chronically progredient kidney alterations, which predominantly affect the glomerula in symptomatic cases. IgG rheuma factors do not seem to play a role in filarial infection associated renal disease. DEC-treatment indeed did not significantly alter degree and character of the proteinuria, but relatively high albumin levels in the urine of treated persons yet suggest increased glomerular disorders in these cases. In conclusion, renal disease appears to be a common event in Brugia filariasis; involving both the tubular and glomerular compartment of the organ its pathogenesis is obviously complex and not only immune complex-mediated.

Acetylglucosaminidase↗

PubMed2000

Functional retinoid receptors in budding ascidians.

A homolog of retinoid X receptors (RXR), named PmRXR, was cloned from the budding ascidian, Polyandrocarpa misakiensis. Gel-shift assays revealed that PmRXR and a previously identified P. misakiensis retinoic acid receptor (PmRAR) formed a complex to bind vertebrate-type retinoic acid response element (RARE). Transfection assays were carried out using a reporter gene containing a RARE upstream of lacZ. Two chimeric effector genes were constructed by placing PmRXR and PmRAR cDNA fragments (containing the DNA-binding, ligand-binding and ligand-dependent transactivation domains) downstream of the human RXR alpha and RAR alpha cDNA (covering the N-terminal coding region), respectively. Each chimeric cDNA was ligated to a notochord-specific enhancer. In case the embryos were transfected with all three transgenes and treated with retinoic acid (RA), the reporter gene was activated in the notochord cells. The result suggests that the PmRXR/PmRAR complex functions as an RA-dependent transcriptional activator. The PmRXR mRNA was detected in a mesenchymal cell type, called glomerulocyte, in the developing Polyandrocarpa bud. As this cell type has been shown to express PmRAR mRNA, it seems possible that the PmRXR/PmRAR complex mediates RA signaling in this cell type to induce the expression of genes involved in the morphogenesis of the developing bud.

Amino Acid Sequence↗