Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.2.3.23 (GAS)
 957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed small peptide mimetics of gamma interferon (IFNgamma), based not on the classical model of IFNgamma initiated signaling by extracellular interaction, but rather on direct intracellular signaling by IFNgamma. IFNgamma, its receptor subunit IFNGR1, and transcription factor STAT1alpha are transported to the nucleus of cells as a complex where IFNgamma provides a classical polycationic nuclear localization sequence (NLS) for such transport. The C terminus of IFNgamma, represented here by the mouse IFNgamma peptide, IFNgamma(95-132), was capable of also forming a complex with IFNGR1 and STAT1alpha when introduced intracellularly and provided the NLS signaling for nuclear transport. Importantly, mouse IFNgamma(95-132) and human IFNgamma(95-134) mimetics both induced an antiviral state and upregulation of MHC class II molecules in cells similar to that of full length IFNgamma. Both IFNgamma and its peptide mimetics bind to an intracellular site, IFNGR1(253-287), on the cytoplasmic domain of receptor subunit IFNGR1. This binding plays a role in tyrosine phosphorylation events, catalyzed by JAK1 and JAK2 kinases that result in the phosphorylation and binding of STAT1alpha to the cytoplasmic domain of IFNGR1. Important structural requirements for IFNgamma mimetic activity are a polycationic NLS and an alpha helix in the mimetics. Finally, chromatin immunoprecipitations and reporter gene studies of IFNgamma and IFNgamma mimetic treated cells indicate that they, along with IFNGR1 and STAT1alpha, bind to the GAS element of IFNgamma activated genes and participate in STAT1alpha transcription. It is important to note that IFNgamma intracellular events played the key role in development of IFNgamma mimetics.
Cell Mol Biol (Noisy-le-grand) 2006 May 15
PMID:Gamma interferon signaling: insights to development of interferon mimetics. 1691 98

The MHC class II transactivator (CIITA) acts in the cell nucleus as the master regulator of MHC class II (MHC II) gene expression. It is important to study CIITA regulation in multiple myeloma since MHC expression is central to ability of myeloma cells to present antigen and to the ability of the immune system to recognize and destroy this malignancy. Regulation of CIITA by IFN-gamma in B lymphocytes occurs through the CIITA type IV promoter (pIV), one of the four potential promoters (pI-pIV) of this gene. To investigate regulation of CIITA by IFN-gamma in multiple myeloma cells, first the ability of these cells to respond to IFN-gamma was examined. RT-PCR analyses show that IFN-gammaR1, the IFN-gamma-binding chain of the IFN-gamma receptor, is expressed in myeloma cells and IRF-1 expression increases in response to IFN-gamma treatment. Western blotting demonstrates that STAT1 is activated by phosphorylation in response to IFN-gamma. RT-PCR and functional promoter analyses show that IFN-gamma upregulates the activity of CIITA pIV, as does ectopic expression of IRF-1 or IRF-2. In vivo protein/DNA binding studies demonstrate protein binding at the GAS, E box and IRF-E sites. In vitro studies confirm the binding of IRF-1 and IRF-2 to CIITA pIV. Although multiple myeloma cells express PRDI-BF1/Blimp-1, a factor that represses both the CIITA type III and IV promoters, they retain the capability to upregulate CIITA pIV and MHC II expression in response to IFN-gamma treatment. These findings are the first to demonstrate that although PRDI-BF1/Blimp-1 diminishes the constitutive ability of these cells to present antigen by limiting CIITA and MHC II expression, it is possible to enhance this expression through the use of cytokines, like IFN-gamma.
Mol Immunol 2007 Apr
PMID:MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-gamma. 1730 Aug 40

Group A Streptococcus (GAS, Streptococcus pyogenes) is a Gram-positive human pathogen responsible for several acute diseases and autoimmune sequelae that account for half a million deaths worldwide every year. GAS infections require the capacity of the pathogen to adhere to host tissues and assemble in cell aggregates. Furthermore, a role for biofilms in GAS pathogenesis has recently been proposed. Here we investigated the role of GAS pili in biofilm formation. We demonstrated that GAS pilus-negative mutants, in which the genes encoding either the pilus backbone structural protein or the sortase C1 have been deleted, showed an impaired capacity to attach to a pharyngeal cell line. The same mutants were much less efficient in forming cellular aggregates in liquid culture and microcolonies on human cells. Furthermore, mutant strains were incapable of producing the typical three-dimensional layer with bacterial microcolonies embedded in a carbohydrate polymeric matrix. Complemented mutants had an adhesion and aggregation phenotype similar to the wild-type strain. Finally, in vivo expression of pili was indirectly confirmed by demonstrating that most of the sera from human patients affected by GAS-mediated pharyngitis recognized recombinant pili proteins. These data support the role of pili in GAS adherence and colonization and suggest a general role of pili in all pathogenic streptococci.
Mol Microbiol 2007 May
PMID:Streptococcus pyogenes pili promote pharyngeal cell adhesion and biofilm formation. 1750 21

Co-ordinate regulation of virulence gene expression in response to different host environments is central to the success of the group A streptococcus (GAS, Streptococcus pyogenes) as an important human pathogen. Mga represents a ubiquitous stand-alone virulence regulator that controls genes (Mga regulon) whose products are necessary for adherence, internalization and host immune evasion. Mga highly activates a core set of virulence genes, including its own gene, by directly binding to their promoters. Yet, Mga also influences expression of over 10% of the GAS genome, primarily genes and operons involved in metabolism and sugar utilization. Expression of the Mga regulon is influenced by conditions that signify favourable growth conditions, presumably allowing GAS to take advantage of promising new niches in the host. The ability of Mga to respond to growth signals clearly involves regulation of mga expression via global regulatory networks such as RALPs, Rgg/RopB and the catabolite control protein CcpA. However, the presence of predicted PTS regulatory domains (PRDs) within Mga suggests an intriguing model whereby phosphorylation of Mga by the PTS phosphorelay might link growth and sugar utilization with virulence in GAS. As Mga homologues have been found in several important Gram-positive pathogens, the Mga regulon could provide a valuable paradigm for increasing our understanding of global virulence networks in bacteria.
Mol Microbiol 2007 Dec
PMID:The Mga virulence regulon: infection where the grass is greener. 1800 46

The CovR/S two-component system regulates the transcription of many genes that are crucial for the virulence of Streptococcus pyogenes (group A Streptococcus, GAS). Previously, we demonstrated that one gene repressed directly by CovR is rivR, which encodes a member of the RofA-like family of transcriptional regulators. In this study, we deleted rivR and its downstream gene rivX in a DeltacovR background. Microarray analysis revealed that the products of the rivRX locus exert positive control over the transcription of members of the Mga regulon. Using mutational analysis, we established that rivX encodes a small regulatory RNA. We found that RivR enhances transcriptional activation by Mga in vivo and in vitro. An M1 DeltacovRDeltarivRX strain is attenuated for virulence in a murine model of invasive soft tissue infection and this attenuation is complemented by rivRX expressed from a plasmid, demonstrating the importance of the rivRX locus in pathogenesis. This study provides the first link between the CovR and Mga regulatory networks. By integrating the signals received through these two global regulators, GAS is able to select from its repertoire different combinations of specific virulence factors to express in response to a broad spectrum of environmental conditions.
Mol Microbiol 2007 Dec
PMID:RivR and the small RNA RivX: the missing links between the CovR regulatory cascade and the Mga regulon. 1800

Reporter constructs of three interferon (IFN)-gamma-induced rainbow trout genes were generated to examine specificity to type I or type II IFN. Constructs included gammaIP-10, LMP2 and TAP2 and were used to transfect trout fibroblast cells (RTG-2) which were then exposed to rainbow trout rIFNs. The gammaIP-10 construct showed high reporter activity even in the absence of rIFNs. The LMP2 promoter contained one GAS element and two double ISRE elements, of four constructs made, only those with ISRE elements showed significant reporter activity following rIFN-gamma stimulation. The TAP2 regulatory region contained two GAS, two ISRE and one C/EBP element from which four constructs were made. Reporter expression for the construct containing all five elements showed an 11- and 2-fold increase in response to rIFN-gamma and type I rIFN, respectively. Constructs containing only the GAS elements did not respond to rIFNs. The TAP2 construct with two ISRE and the C/EBP gave the greatest dose-dependent reporter response to rIFN-gamma, with no significant response to type I rIFN. These data suggest that the ISRE elements, or elements nearby, are essential for the induction of type II IFN responsive genes in trout. The TAP2 construct is a candidate to develop a IFN-gamma reporter stable cell line.
Mol Immunol 2008 Jul
PMID:Characterisation of gamma-interferon responsive promoters in fish. 1845 79

We previously demonstrated that the cell-surface lipoprotein MalE contributes to GAS maltose/maltodextrin utilization, but MalE inactivation does not completely abrogate GAS catabolism of maltose or maltotriose. Using a genome-wide approach, we identified the GAS phosphotransferase system (PTS) responsible for non-MalE maltose/maltotriose transport. This PTS is encoded by an open reading frame (M5005_spy1692) previously annotated as ptsG based on homology with the glucose PTS in Bacillus subtilis. Genetic inactivation of M5005_spy1692 significantly reduced transport rates of radiolabelled maltose and maltotriose, but not glucose, leading us to propose its reannotation as malT for maltose transporter. The DeltamalT, DeltamalE and DeltamalE:malT strains were significantly attenuated in their growth in human saliva and in their ability to catabolize alpha-glucans digested by purified human salivary alpha-amylase. Compared with wild-type, the three isogenic mutant strains were significantly impaired in their ability to colonize the mouse oropharynx. Finally, we discovered that the transcript levels of maltodextrin utilization genes are regulated by competitive binding of the maltose repressor MalR and catabolite control protein A. These data provide novel insights into regulation of the GAS maltodextrin genes and their role in GAS host-pathogen interaction, thereby increasing the understanding of links between nutrient acquisition and virulence in common human pathogens.
Mol Microbiol 2008 Jul
PMID:Molecular characterization of group A Streptococcus maltodextrin catabolism and its role in pharyngitis. 1848 73

We developed molecular diagnostic assays for the detection of Streptococcus pyogenes (GAS) and Streptococcus dysgalactiae subsp. equisimilis (SDSE), two streptococcal pathogens known to cause both pharyngitis and more invasive forms of disease in humans. Two real-time PCR assays coupled with an internal control were designed to be performed in parallel. One assay utilizes a gene target specific to GAS, and the other utilizes a gene target common to the two species. Both assays showed 2-3 orders of magnitude improved analytical sensitivity when compared to a commercially available rapid antigen test. In addition, when compared to standard culture in an analysis of 96 throat swabs, the real-time PCR assays resulted in clinical sensitivity and specificity of 91.7 and 100%, respectively. As capital equipment costs for real-time PCR can be prohibitive in smaller laboratories, the real-time PCR assays were converted to a low-density microarray format designed to function with an inexpensive photopolymerization-based non-enzymatic signal amplification (NESA) method. S. pyogenes was successfully detected on the low-density microarray in less than 4 h from sample extraction through detection.
Mol Biotechnol 2009 May
PMID:Molecular detection of Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis. 1915 48

The Janus kinases (JAK) and signal transducer and activator of transcription (STAT) signaling are strongly activated in many tumors. STAT proteins are activated by phosphorylation at the tyrosine residue, then dimerize, translocate to the nucleus and bind DNA, initiating the transcription of target genes. Activation of JAK-STAT pathway is implicated in the regulation of cell growth, differentiation, survival and cross-talk between cancer and immune cells. The activation of STATs depends on phosphorylation on a single tyrosine residue (e.g., Tyr705 in STAT3 and Tyr694 in STAT5) in the C-terminal domain. Commercially available antibodies discriminate between total and specifically phosphorylated (active) forms of different STATs, which allows to measure directly STATs activation in crude cell extracts. Nuclear translocation and transcriptional activity of STATs can be measured in transfected cells using STAT dependent promoter driving reporter luciferase gene. STAT signaling pathway and STAT-dependent gene expression in cells can be specifically modulated using oligodeoxynucleotide (ODN) STAT decoy which is a double-stranded fragment of DNA containing an overlapping ISRE/GAS binding site.
Methods Mol Biol 2009
PMID:Molecular characterization of STAT signaling in inflammation and tumorigenesis. 1934 82

The important human pathogen Streptococcus pyogenes (group A streptococcus, GAS) initiates infection by pilus-mediated attachment to host tissue. Thus, the pilus is an excellent target for design of anti-infective strategies. The T3 pilus of GAS is composed of multiple covalently linked subunits of the T3 protein to which the two minor pilins, Cpa and OrfB, are covalently attached. Because the proteins of GAS pili do not contain either of the motifs required for pilus polymerization in other Gram-positive bacteria, we investigated the residues involved in their linkage. We show that linkage of Cpa to T3 by the sortase family transpeptidase SrtC2 requires the VPPTG motif in the cell wall-sorting signal of Cpa. We also demonstrate that K173 of T3 is required both for T3 polymerization and for attachment of Cpa to T3. Therefore, attachment of Cpa to K173 of a T3 subunit would block further addition of T3 subunits to this end of the growing pilus. This implies that Cpa is located exclusively at the pilus tip, a location supported by immunogold electron microscopy, and suggests that, as for well-studied pili on Gram-negative bacteria, the role of the pilus is to present the adhesin external to the bacterial capsule.
Mol Microbiol 2009 Jun
PMID:Linkage of T3 and Cpa pilins in the Streptococcus pyogenes M3 pilus. 1943 98


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