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PubMed2004

Fc gamma RIIa polymorphism: a susceptibility factor for immune complex-mediated lupus nephritis in Brazilian patients.

BACKGROUND: Fc gamma RIIa is a low affinity receptor that has two co-dominantly expressed alleles, R131 and H131, which differ in their ability to bind immunoglobulin G (IgG) subclasses. Cells expressing H131 bind more efficiently complexed IgG2 and IgG3 than those expressing the R131 variant. The Fc gamma RIIa polymorphism has been shown to be associated with lupus nephritis. Here we evaluated the relevance of Fc gamma RIIa gene polymorphism in the development of lupus immune complex (IC)-mediated nephritis by comparing the genotype and allelic distribution of this receptor in lupus nephritis to ethnically matched healthy controls in Brazilians. METHODS: 119 systemic lupus erythematosus (SLE) patients and 48 healthy volunteers were recruited. Fc gamma RIIa genotyping was performed by PCR with allele-specific primers to distinguish between the two allelic forms (H131 and R131). RESULTS: Comparison of Fc gamma RIIa genotypes distribution in SLE patients with nephritis and in controls showed a significant increase in Fc gamma RIIa-R131 homozygosity (P < or = 0.02). The genotype distribution in lupus nephritis (45% with Fc gamma RIIa-R/R131, 30% with H/R131 and 25% with H/H131) was distinct from that observed in controls (21% with Fc gamma RIIa-R/R131, 52% with H/R131 and 27% with H/H131). In contrast, there was no difference in the distribution of Fc gamma RIIa genotypes in lupus without nephritis and controls (P = 0.3). Reinforcing the relevance of Fc gamma RIIa polymorphism in IC-mediated nephritis, patients with renal failure had an over-representation of the R131 allele (70%) when compared with normal controls (47%) (P = 0.06). CONCLUSIONS: The skewed distribution of Fc gamma RIIa genotypes with the predominance of homozygous R/R131 genotype observed in lupus nephritis emphasizes its importance as a heritable risk factor for IC-mediated renal injury in Brazilian lupus patients.

Alleles↗
PubMed1993

Distinct TFIID complexes mediate the effect of different transcriptional activators.

Multiple chromatographically separable complexes containing the TATA binding protein (TBP), which exhibit different functional properties, exist in HeLa cells. At least three distinct subpopulations of such complexes can be functionally defined as TFIID since they function with RNA polymerase II. Using a partially reconstituted HeLa cell in vitro transcription system and immunoprecipitation with a monoclonal antibody directed against TBP, we show that stimulation of transcription by the chimeric activators GAL-VP16, GAL-TEF-1 and GAL-ER(EF) requires the presence of factors which are tightly associated with these TFIID complexes. Moreover, the activity of GAL-TEF-1 appears to be mediated by at least two chromatographically distinct populations of TFIID. The factor(s) associated with one of these populations is also required for the activity of GAL-ER (EF) and GAL-VP16, while the factor(s) associated with the other population functions selectively with GAL-TEF-1. These two TFIID populations are composed of both common and unique TBP associated factors (TAFs).

Animals↗
PubMed2004

Ferromagnetic exchange in a dinuclear copper(II) complex mediated by a methanolate bridging ligand.

The copper(II) complex Cu(2)L(OMe)(H(2)O)(3), [middle dot]3H(2)O [H(3)L = 2-(2-hydroxyphenyl)-1,3-bis[4-(2-hydroxyphenyl)-3-azabut-3-enyl]-1,3-imidazolidine] was obtained and recrystallised in methanol to yield crystals of [[Cu(2)L(OMe)]](2).2.5MeOH.4H(2)O, 1.2.5MeOH.4H(2)O. Its single X-ray study shows that it contains two crystallographically different but chemically equivalent dinuclear [Cu(2)L(OMe)] 1 molecules in the asymmetric unit cell. The copper atoms of each dinuclear moiety are in distorted square-pyramidal environments, with both pyramids sharing an apical phenolate and a basal methanolate oxygen atom. Magnetic characterisation of 1.3H(2)O shows a quite strong intramolecular ferromagnetic coupling between both metal atoms. Extended Huckel calculations reveal that the intradinuclear magnetic interaction seems to be mediated by the exogenous methanolate bridging ligand.

Journal Article↗
PubMed1995

Clostridial neurotoxins compromise the stability of a low energy SNARE complex mediating NSF activation of synaptic vesicle fusion.

A 20S complex composed of the cytosolic fusion proteins NSF and SNAP and the synaptosomal SNAP receptors (SNAREs) synaptobrevin, syntaxin and SNAP-25 is essential for synaptic vesicle exocytosis. Formation of this complex is thought to be regulated by synaptotagmin, the putative calcium sensor of neurotransmitter release. Here we have examined how different inhibitors of neurotransmitter release, e.g. clostridial neurotoxins and a synaptotagmin peptide, affect the properties of the 20S complex. Cleavage of synaptobrevin and SNAP-25 by the neurotoxic clostridial proteases tetanus toxin and botulinum toxin A had no effect on assembly and disassembly of the 20S complex; however, the stability of its SDS-resistant SNARE core was compromised. This SDS-resistant low energy conformation of the SNAREs constitutes the physiological target of NSF, as indicated by its ATP-dependent disassembly in the presence of SNAP and NSF. Synaptotagmin peptides caused inhibition of in vitro binding of this protein to the SNAREs, a result that is inconsistent with synaptotagmin's proposed role as a regulator of SNAP binding. Our data can be reconciled by the idea that NSF and SNAP generate synaptotagmin-containing intermediates in synaptic vesicle fusion, which catalyse neurotransmitter release.

Adenosine Triphosphate↗
PubMed1989

Evidence of a precursor-product relationship between vitellogenin and toposome, a glycoprotein complex mediating cell adhesion.

Toposome, a large and oligomeric glycoprotein complex isolated from mesenchyme-blastula embryos, was defined as a cell-adhesion molecule expressing positional information specificities during sea urchin embryogenesis. This report describes the biochemical and functional characterization of the toposome precursor from sea urchin coelomic fluids of both male and female organisms. The molecule is isolated in the form of a 22S particle which has an apparent molecular mass of 200 kDa. An intermediate form is present in yolk granules of unfertilized eggs with a molecular mass of 180 kDa. The 200 kDa and 180 kDa polypeptides are defined as toposome precursors by Western blot and immunoprecipitation analyses using polyclonal and monoclonal toposome-specific antibodies. Comparison of the 200 kDa polypeptide and mesenchyme-blastula toposome by partial-proteolysis peptide-mapping shows that they are related in a precursor-product relationship. A morphogenetic cell-aggregation assay shows that toposome precursors promote cell adhesion of dissociated blastula cells, suggesting that processing is not required for the cell-adhesion function. The studies reported here present the first evidence that cell adhesion molecules first appear in the form of a 200 kDa polypeptide, previously named vitellogenin, and to which only a function as major-yolk-protein precursor has been ascribed.

Animals↗
PubMed2001

Drosophila Mediator complex is broadly utilized by diverse gene-specific transcription factors at different types of core promoters.

To decipher the mechanistic roles of Mediator proteins in regulating developmental specific gene expression and compare them to those of TATA-binding protein (TBP)-associated factors (TAFs), we isolated and analyzed a multiprotein complex containing Drosophila Mediator (dMediator) homologs. dMediator interacts with several sequence-specific transcription factors and basal transcription machinery and is critical for activated transcription in response to diverse transcriptional activators. The requirement for dMediator did not depend on a specific core promoter organization. By contrast, TAFs are preferentially utilized by promoters having a specific core element organization. Therefore, Mediator proteins are suggested to act as a pivotal coactivator that integrates promoter-specific activation signals to the basal transcription machinery.

Amino Acid Sequence↗
PubMed2003

The inhibitory receptor FcgammaRII reduces joint inflammation and destruction in experimental immune complex-mediated arthritides not only by inhibition of FcgammaRI/III but also by efficient clearance and endocytosis of immune complexes.

Studies of FcgammaRII-/- mice identified the inhibitory function of this receptor in joint inflammation and cartilage destruction induced with immune complexes (ICs). To extend our insight in the role of FcgammaRII in arthritis, we explored the role of FcgammaRII in the absence of activating receptors I and III using FcgammaRI/III-/- as well as FcgammaRI/II/III-/- mice. When antigen-induced arthritis (AIA) was elicited, which is a mixture of T cell and IC-driven inflammation, arthritis was almost absent at day 7 in FcgammaRI/III-/- mice. Remarkably, in FcgammaRI/II/III-/- mice, this model induced a tremendously increased arthritis as compared to wild-type controls. This implies that FcgammaRII regulates joint inflammation also in the absence of activating FcgammaRI and III. To confirm the IC specificity of this finding, similar studies were done with ICs or zymosan as arthritogenic stimuli. Strongly elevated inflammation was found in FcgammaRI/II/III-/- mice with IC but not with zymosan. Clearance studies identified accumulation of IgG in the knee joint in the absence of FcgammaRII. Moreover, macrophages expressing only FcgammaRII showed prominent endocytosis of preformed soluble ICs not different from controls. In total absence of FcgammaR (FcgammaRI/II/III-/-), macrophages completely failed to endocytose ICs. Although joint inflammation was much higher in AIA arthritic knee joints of FcgammaRI/II/III-/- and the inflammatory cells still expressed an inflammatory phenotype, severe cartilage destruction (MMP-mediated neoepitopes in the matrix and chondrocyte death) was completely prevented in contrast to the marked destruction which was observed in the wild-type. Our study indicates that FcgammaRII reduces joint inflammation in the absence of activating FcgammaR by promoting endocytosis and clearance of ICs from the joint. Infiltrating cells, which fail to express activating FcgammaR although they still become stimulated are no longer capable of inducing severe cartilage destruction.

Animals↗
PubMed2000

Differential effects of interferon-gamma on metabolism of lipoprotein immune complexes mediated by specific human macrophage Fcgamma receptors.

The objectives were to determine whether there are differences in the mechanisms of lipoprotein metabolism associated with different FcgammaRs and how metabolism associated with FcgammaRs compares to that mediated by scavenger receptors (SRA). To analyze lipoprotein metabolism in a receptor-specific manner, bispecific antibodies were used to target low density lipoproteins (LDL) labeled with (125)I or [(3)H]cholesterol linoleate to FcgammaRI or FcgammaRIIA in human macrophages. Interferon-gamma (IFN-gamma), which stimulates expression of FcgammaRI while inhibiting expression of SRA, was used to help delineate differences in metabolism between each receptor. For each receptor, the total amount of lipoprotein degradation paralleled changes in receptor expression induced by IFN-gamma. In particular, while SRA-mediated degradation typically exceeded degradation mediated by FcgammaRI, in IFN-gamma-treated cells degradation associated with FcgammaRI and SRA was similar. Assay of [(3)H]cholesterol linoleate-labeled lipoproteins indicated that total uptake and hydrolysis of [(3)H]cholesterol linoleate was similar for each class of receptor, and inhibited by IFN-gamma. For FcgammaRI versus FcgammaRIIA, in the presence or absence of IFN-gamma, the [(3)H]cholesterol derived from FcgammaRIIA-mediated uptake was preferentially targeted for re-esterification to [(3)H]cholesterol oleate, in comparison to that resulting from hydrolysis of [(3)H]cholesterol linoleate incorporated by selective uptake. For SRA, the formation of [(3)H]cholesterol oleate, which was substantial in control cells, was significantly inhibited in the presence of IFN-gamma. We conclude that there may be differences in cholesterol trafficking with respect to lipoprotein immune complex metabolism mediated by different classes of FcgammaRs.

Antigen-Antibody Complex↗
PubMed2000

A SNARE complex mediating fusion of late endosomes defines conserved properties of SNARE structure and function.

Sets of SNARE proteins mediate membrane fusion by assembling into core complexes. Multiple SNAREs are thought to function in different intracellular trafficking steps but it is often unclear which of the SNAREs cooperate in individual fusion reactions. We report that syntaxin 7, syntaxin 8, vti1b and endobrevin/VAMP-8 form a complex that functions in the fusion of late endosomes. Antibodies specific for each protein coprecipitate the complex, inhibit homotypic fusion of late endosomes in vitro and retard delivery of endocytosed epidermal growth factor to lysosomes. The purified proteins form core complexes with biochemical and biophysical properties remarkably similar to the neuronal core complex, although each of the four proteins carries a transmembrane domain and three have independently folded N-terminal domains. Substitution experiments, sequence and structural comparisons revealed that each protein occupies a unique position in the complex, with syntaxin 7 corresponding to syntaxin 1, and vti1b and syntaxin 8 corresponding to the N- and C-terminal domains of SNAP-25, respectively. We conclude that the structure of core complexes and their molecular mechanism in membrane fusion is highly conserved between distant SNAREs.

Amino Acid Sequence↗
PubMed2000

Immune complex mediated lesions in experimental Kala azar: an ultrastructural study.

Immune complexes play an important role in causation of renal lesions in various diseases. Circulating immune comlexes (CIC) are described in Kala azar. Role of CIC in pathogenesis of Kalaazar is discussed in present study. BALB/C mice were experimentally infected with L. donovani promastigotes. After visceralisation of infection, sera and kidneys of infected mice were preserved. Leishmanial antigen specific CIC could be demonstrated in 100% of infected mice by PEG ELISA, while they were absent in control mice. Ultrastructural pattern of renal lesions in infected mice showed presence of focal small electron dense deposits in glomerular basement membrane and subepithelial space, resembling immune complexes (humps). Rarely subendothelial and mesangial hypercellularity was present. These findings point towards a definite role of CIC in pathogenesis of renal lesions in Kalaazar.

Animals↗
PubMed1998

Molecular mechanism governing heme signaling in yeast: a higher-order complex mediates heme regulation of the transcriptional activator HAP1.

Apart from serving as a prosthetic group in globins and enzymes, heme is a key regulator controlling a wide range of molecular and cellular processes involved in oxygen sensing and utilization. To gain insights into molecular mechanisms of heme signaling and oxygen sensing in eukaryotes, we investigated the yeast heme-responsive transcriptional activator HAP1. HAP1 activity is regulated precisely and tightly by heme. Here we show that in the absence of heme, HAP1 forms a biochemically distinctive higher-order complex. Our data suggest that this complex contains HAP1 and four other cellular proteins including Hsp82 and Ydj1. The formation of this complex is directly correlated with HAP1 repression in the absence of heme, and mutational or heme disruption of the complex correlates with HAP1 activation, suggesting that this complex is responsible for heme regulation of HAP1 activity. Further, we determined HAP1 domains required for heme regulation: three domains-the dimerization domain, the heme domain, and the HRM7 (heme-responsive motif 7) domain-cooperate to form the higher-order complex and mediate heme regulation. Strikingly, we uncovered a novel function for the HAP1 dimerization domain: it not only allows dimerization but also provides critical functions in heme regulation and transcriptional activation. Our studies provide significant insights into the molecular events leading to heme activation of HAP1 and may shed light on molecular mechanisms of various heme-controlled biological processes in diverse organisms.

Animals↗
PubMed2002

Fear memory formation involves p190 RhoGAP and ROCK proteins through a GRB2-mediated complex.

We used fear conditioning, which is known to alter synaptic efficacy in lateral amygdala (LA), to study molecular mechanisms underlying long-term memory. Following fear conditioning, the tyrosine phosphorylated protein p190 RhoGAP becomes associated with GRB2 in LA significantly more in conditioned than in control rats. RasGAP and Shc were also found to associate with GRB2 in LA significantly more in the conditioned animals. Inhibition of the p190 RhoGAP-downstream kinase ROCK in LA during fear conditioning impaired long- but not short-term memory. Thus, the p190 RhoGAP/ROCK pathway, which regulates the morphology of dendrites and axons during neural development, plays a central role, through a GRB2-mediated molecular complex, in fear memory formation in the lateral amygdala.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Ctk complex-mediated regulation of histone methylation by COMPASS.

A comparative global proteomic screen identified factors required for COMPASS (complex of proteins associated with Set1)-mediated mono-, di-, and trimethylation of the fourth lysine of histone H3 (H3K4), which included components of a cyclin-dependent protein kinase (Ctk complex) that phosphorylates the C-terminal domain of the largest subunit of RNA polymerase II (Pol II). Our results indicate that histone H3K4 methylation levels are regulated by the Ctk1, Ctk2, and Ctk3 components of the Ctk complex. We show that loss of Ctk1 kinase activity results in reduced histone H3K4 monomethylation levels, followed by a global increase in histone H3K4 trimethylation levels on chromatin. Ctk1 loss does not appear to have a substantial effect on histone H2B monoubiquitination levels or COMPASS and Paf1 complex phosphorylation. Our chromatin immunoprecipitation studies demonstrate that histone H3 eviction during active transcription is decelerated in a CTK1 deletion strain in response to reduced levels of Pol II recruitment. Our in vitro studies show that the onset of monomethylation on an unmethylated histone H3 by COMPASS is virtually immediate, while the onset of trimethylation occurs upon extended time of association between the histone tail and COMPASS. Our study suggests a role for the Ctk complex in the regulation of the pattern of H3K4 mono-, di-, and trimethylation via COMPASS.

Chromatin Immunoprecipitation↗
PubMed2007

A structured viroid RNA serves as a substrate for dicer-like cleavage to produce biologically active small RNAs but is resistant to RNA-induced silencing complex-mediated degradation.

RNA silencing is a potent means of antiviral defense in plants and animals. A hallmark of this defense response is the production of 21- to 24-nucleotide viral small RNAs via mechanisms that remain to be fully understood. Many viruses encode suppressors of RNA silencing, and some viral RNAs function directly as silencing suppressors as counterdefense. The occurrence of viroid-specific small RNAs in infected plants suggests that viroids can trigger RNA silencing in a host, raising the question of how these noncoding and unencapsidated RNAs survive cellular RNA-silencing systems. We address this question by characterizing the production of small RNAs of Potato spindle tuber viroid (srPSTVds) and investigating how PSTVd responds to RNA silencing. Our molecular and biochemical studies provide evidence that srPSTVds were derived mostly from the secondary structure of viroid RNAs. Replication of PSTVd was resistant to RNA silencing, although the srPSTVds were biologically active in guiding RNA-induced silencing complex (RISC)-mediated cleavage, as shown with a sensor system. Further analyses showed that without possessing or triggering silencing suppressor activities, the PSTVd secondary structure played a critical role in resistance to RISC-mediated cleavage. These findings support the hypothesis that some infectious RNAs may have evolved specific secondary structures as an effective means to evade RNA silencing in addition to encoding silencing suppressor activities. Our results should have important implications in further studies on RNA-based mechanisms of host-pathogen interactions and the biological constraints that shape the evolution of infectious RNA structures.

Arabidopsis↗
PubMed2004

IXL, a new subunit of the mammalian Mediator complex, functions as a transcriptional suppressor.

Transcription factors play an essential role in altering gene expression. Much progress about transcription factors has been made toward the understanding of normal physiological processes, embryonic development, and human diseases. In the present study, we report the identification and characterization of a novel human gene, (Drosophila) intersex-like (IXL), from a human embryonic heart cDNA library. IXL encodes a putative protein of 221 amino acids. The protein is conserved across different species during evolution. Northern blot analysis indicates that IXL is expressed in various tissues of human adult and during three different developmental stages of embryo. In COS-7 cells, IXL protein is localized to nucleus and cytoplasm. IXL is a transcription suppressor when fused to Gal-4 DNA-binding domain and cotransfected with VP-16. Overexpression of IXL in COS-7 cells inhibits the transcriptional activities of SRE and AP-1, suggesting that the IXL protein may act as a transcriptional suppressor in mitogen-activated protein kinase signaling pathway to mediate cellular functions.

Amino Acid Sequence↗
PubMed2001

Use of complement receptor 1 (CD35) assay in the diagnosis and prognosis of immune complex mediated glomerulopathies.

Complement Receptor 1 (CR1) is a polymorphic glycoprotein expressed on erythrocytes, leukocytes and glomerular podocytes and has a major role in immune complex processing. In addition, it regulates the complement cascade activation by preventing formation of classical and alternative pathway convertases and by acting as a cofactor for Factor I mediated cleavage of C3. In this study, we have examined the expression of erythrocyte CR1 (E-CR1) and glomerular CR1 (G-CR1) in different kinds of nephropathies using ELISA and immunofluorescence microscopy to understand their role in immune complex (IC) mediated renal diseases. E-CR1 was significantly reduced in all categories of lupus nephritis in comparison to normal subjects and non-IC renal diseases. However, other IC mediated diseases like IgA nephropathy and membranoproliferative glomerulonephritis had normal E-CR1 levels. G-CR1 showed distinct differences between IC and non-IC mediated diseases. G-CR1 was virtually absent in lupus kidneys. In other IC mediated diseases, there was a correlation of G-CR1 expression to the IC and complement fragment deposition. G-CR1 serves as a useful diagnostic marker for IC mediated diseases while E-CR1 is useful as a prognostic marker to monitor the course of disease after the treatment has initiated.

Erythrocytes↗
PubMed2005

Contribution of CAF-I to anaphase-promoting-complex-mediated mitotic chromatin assembly in Saccharomyces cerevisiae.

The anaphase-promoting complex (APC) is required for mitotic progression and genomic stability. Recently, we demonstrated that the APC is also required for mitotic chromatin assembly and longevity. Here, we investigated the role the APC plays in chromatin assembly. We show that apc5(CA) mutations genetically interact with the CAF-I genes as well as ASF1, HIR1, and HIR2. When present in multiple copies, the individual CAF-I genes, CAC1, CAC2, and MSI1, suppress apc5(CA) phenotypes in a CAF-1- and Asf1p-independent manner. CAF-I and the APC functionally overlap, as cac1delta cac2delta msi1delta (caf1delta) cells expressing apc5(CA) exhibit a phenotype more severe than that of apc5(CA) or caf1delta. The Ts- phenotypes observed in apc5(CA) and apc5(CA) caf mutants may be rooted in compromised histone metabolism, as coexpression of histones H3 and H4 suppressed the Ts- defects. Synthetic genetic interactions were also observed in apc5(CA) asf1delta cells. Furthermore, increased expression of genes encoding Asf1p, Hir1p, and Hir2p suppressed the apc5(CA) Ts- defect in a CAF-I-dependent manner. Together, these results suggest the existence of a complex molecular mechanism controlling APC-dependent chromatin assembly. Our data suggest the APC functions with the individual CAF-I subunits, Asf1p, and the Hir1p and Hir2p proteins. However, Asf1p and an intact CAF-I complex are dispensable for CAF-I subunit suppression, whereas CAF-I is necessary for ASF1, HIR1, and HIR2 suppression of apc5(CA) phenotypes. We discuss the implications of our observations.

Anaphase-Promoting Complex-Cyclosome↗
PubMed1980

Studies of lymphocytotoxins in infectious mononucleosis and systemic lupus erythematosus: evidence for immune complex-mediated cytotoxicity.

The hypothesis that serum lymphocytotoxins are antigen-antibody complexes was examined. High molecular weight fractions from the sera of eighteen patients with infectious mononucleosis (IM), thirteen patients with systemic lupus erythematosus (SLE) and six healthy controls, were prepared by precipitation with polyethylene glycol 6000 (PEG). The lymphocytotoxic activity (LCA) of these PEG precipitates was significantly greater (P less than 0.01) than that of the corresponding sera and a significant correlation (r = 0.66, P less than 0.01) was observed between the LCA of sera and the PEG precipitates. In contrast to the concentration of LCA in the PEG precipitates, the heterophil antibody titres of the precipitates from IM sera were significantly less (P less than 0 05) than serum titres. Antisera raised against PEG precipitates from sera from nine patients with IM contained significant LCA. The nature of this LCA differed from that of the LCA in the original sera in temperature dependence and the molecular size. Antigen-antibody complexes in seven sera (four IM, three SLE) were dissociated at low pH (3.0) and fractionated by gel filtration at pH 3.9. The LCA of these fractions was compared with the LCA of equivalent fractions obtained by gel filtration at pH 7.2. The heterophil antibody present in sera from patients with IM and the cytotoxicity of anti-lymphocyte globulin (ALG) were used as 'antibody controls'. In this way it was shown that the LCA in patient sera, but not heterophil antibody or ALG cytotoxicity was significantly reduced (P less than 0.001) by low pH gel filtration.

Antigen-Antibody Complex↗