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PubMed2000

Effective formation of major histocompatibility complex class II-peptide complexes from endogenous antigen by thyroid epithelial cells.

In autoimmune thyroid disease, thyroid epithelial cells (TEC) express major histocompatibility complex (MHC) class II molecules, potentially enabling them to present thyroid self-antigens to CD4-positive T cells. However, despite this, TEC may fail to present endogenous antigen as a result of limited processing or MHC class II loading capacity, or inadequate MHC class II levels. We addressed these issues using the cloned rat TEC line, Fischer rat thyroid cell line (FRTL5), which was transfected using an adenoviral expression vector that expressed ovalbumin (OVA) as an integral membrane protein. OVA-expressing FRTL5 cells very efficiently activated a panel of OVA-specific, class II-restricted T-cell hybridomas. This response was dependent on induction of MHC class II molecules by interferon-gamma (IFN-gamma) and was blocked by anti-MHC class II antibodies. Poor responses were seen to exogenously added OVA or OVA peptides. These results provide the most direct evidence to date that TEC can form MHC class II-peptide complexes derived from self-antigen in sufficient quantities to activate T cells.

Animals↗
PubMed1998

Molecular remedy of complex I defects: rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria restores the NADH oxidase activity of complex I-deficient mammalian cells.

The NDI1 gene encoding rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria was cotransfected into the complex I-deficient Chinese hamster CCL16-B2 cells. Stable NDI1-transfected cells were obtained by screening with antibiotic G418. The NDI1 gene was shown to be expressed in the transfected cells. The expressed Ndi1 enzyme was recognized to be localized to mitochondria by immunoblotting and confocal immunofluorescence microscopic analyses. Using digitonin-permeabilized cells, it was shown that the transfected cells, but not nontransfected control cells, exhibited the electron transfer activities with glutamate/malate as the respiratory substrate. The activities were inhibited by flavone, antimycin A, and KCN but not by rotenone. Added NADH did not serve as the substrate, suggesting that the expressed Ndi1 enzyme was located on the matrix side of the inner mitochondrial membranes. Furthermore, although nontransfected cells could not survive in a medium low in glucose (0.6 mM), which is a substrate of glycolysis, the NDI1-transfected cells were able to grow in the absence of added glucose. When glycolysis is slow, either at low glucose concentrations or in the presence of galactose, respiration is required for cells to survive. The mutant cells do not survive at low glucose or in galactose, but they can be rescued by Ndi1. These results indicated that the S. cerevisiae Ndi1 was expressed functionally in CCL16-B2 cells and catalyzed electron transfer from NADH in the matrix to ubiquinone-10 in the inner mitochondrial membranes. It is concluded that the NDI1 gene provides a potentially useful tool for gene therapy of mitochondrial diseases caused by complex I deficiency.

Animals↗
PubMed2005

TBP-TAF complex SL1 directs RNA polymerase I pre-initiation complex formation and stabilizes upstream binding factor at the rDNA promoter.

Knowledge of the role of components of the RNA polymerase I transcription machinery is paramount to understanding regulation of rDNA expression. We describe key findings for the roles of essential transcription factor SL1 and activator upstream binding factor (UBF). We demonstrate that human SL1 can direct accurate Pol I transcription in the absence of UBF and can interact with the rDNA promoter independently and stably, consistent with studies of rodent SL1 but contrary to previous reports of human SL1. UBF itself does not bind stably to rDNA but rapidly associates and dissociates. We show that SL1 significantly reduces the rate of dissociation of UBF from the rDNA promoter. Our findings challenge the idea that UBF activates transcription through recruitment of SL1 at the rDNA promoter and suggest that the rate of pre-initiation complex (PIC) formation is primarily determined by the rate of association of SL1, rather than UBF, with the promoter. Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells.

Base Sequence↗
PubMed2004

Biochemical characterization of protein complexes from the Helicobacter pylori protein interaction map: strategies for complex formation and evidence for novel interactions within type IV secretion systems.

We have investigated a large set of interactions from the Helicobacter pylori protein interaction map previously identified by high-throughput yeast two-hybrid (htY2H)-based methods. This study had two aims: i) to validate htY2H as a source of protein-protein interaction complexes for high-throughput biochemical and structural studies of the H. pylori interactome; and ii) to validate biochemically interactions shown by htY2H to involve components of the H. pylori type IV secretion systems. Thus, 17 interactions involving 31 proteins and protein fragments were studied, and a general strategy was designed to produce protein-interacting partners for biochemical and structural characterization. We show that htY2H is a valid source of protein-protein complexes for high-throughput proteome-scale characterization of the H. pylori interactome, because 76% of the interactions tested were confirmed biochemically. Of the interactions involving type IV secretion proteins, three could be confirmed. One interaction is between two components of the type IV secretion apparatus, ComB10 and ComB4, which are VirB10 and VirB4 homologs, respectively. Another interaction is between a type IV component (HP0525, a VirB11 homolog) and a non-type IV secretion protein (HP01451), indicating that proteins other than the core VirB (1-11)-VirD4 proteins may play a role in type IV secretion. Finally, a third interaction was biochemically confirmed between CagA, a virulence factor secreted by the type IV secretion system encoded by the Cag pathogenicity island, and a non-type IV secretion protein, HP0496.

Bacterial Proteins↗
PubMed1980

Growth and reproduction complex in the rat. Genes linked to the major histocompatibility complex that affect development.

The linkage of the major histocompatibility complex (MHC) and the growth and reproduction complex (Grc) in the rat was studied in an F2 hybrid population generated from female BIL/1 (RT1l-Grc) and male YO (RT1u-Grc+) animals: 1.722 offspring were born, and 1,568 were weaned and studied. The body weights of the offspring segregated with the RT1 haplotype of the MHC, and the RT1l homozygotes were significantly smaller than their RT1l/u and RT1u/u littermates. The growth rate of the RT1l/l animals was approximately the same as that of the BIL/1 animals, and both were significantly less than the growth rates of the RT1l/u, RT1u/u, and YO (RT1u) animals. The testes of the RT1l animals showed an arrest of spermatogenesis at the early pachytene stage of the primary spermatocytes, and they were approximately 1/10 as heavy as the testes of the RT1l/u and RT1u/u animals. The ovaries in females of all three haplotypes had the same weight, but there was a decrease in the number of ova released per cycle in the RT1 l/l animals. The major loss of the RT1l homozygotes, which caused distortion of the phenotypic ratios among the offspring, did not occur in utero but in the early postnatal period before weaning. There were 7/1568 recombinants between the MHC, using the RT1.A antigen as the marker, and the Grc, using small body size (dw-3) as the marker, and 1/1568 recombinant between the loci influencing body size (dw-3) and fertility (ft) of the Grc. These data gave the following map distances (95% confidence levels): RT1.A to dw-3, 0.45 (0.25-0.96) centimorgans and dw-3 to ft, 0.07 (0.04-0.40) centimorgans. A female recombinant was used develop an inbred line carrying the RT1.Al-Grc+ chromosome.

Animals↗
PubMed1983

Specificity of T cell clones for antigen and autologous major histocompatibility complex products determines specificity for foreign major histocompatibility complex products.

We have analyzed a panel of T cell clones that corecognize defined epitopes of the insulin molecule in association with Ia for their patterns of recognition of alloantigens. A striking correlation is observed between recognition of the I-Ab gene product and cow insulin alpha loop and recognition of I-Eu of the PL/J haplotype. These results are consistent with the notion that reactions to foreign major histocompatibility complex (MHC) products reflect molecular mimicry by foreign class II antigens of 'physiologic' complexes formed by autologous class II MHC molecules and antigen.

Animals↗
PubMed2003

Human immunodeficiency virus-1 Nef expression induces intracellular accumulation of multivesicular bodies and major histocompatibility complex class II complexes: potential role of phosphatidylinositol 3-kinase.

Nef alters the cell surface expression of several immunoreceptors, which may contribute to viral escape. We show that Nef modifies major histocompatibility complex class II (MHC II) intracellular trafficking and thereby its function. In the presence of Nef, mature, peptide-loaded MHC II were down-modulated at the cell surface and accumulated intracellularly, whereas immature (invariant [Ii] chain-associated) MHC II expression at the plasma membrane was increased. Antibody internalization experiments and subcellular fractionation analyses showed that immature MHC II were internalized from the plasma membrane but had limited access to lysosomes, explaining the reduced Ii chain degradation. Immunoelectron microscopy revealed that Nef expression induced a marked accumulation of multivesicular bodies (MVBs) containing Nef, MHC II, and high amounts of Ii chain. The Nef-induced up-regulation of surface Ii chain was inhibited by LY294002 exposure, indicating the involvement of a phosphatidylinositol 3-kinase, whose products play a key role in MVB biogenesis. Together, our results indicate that Nef induces an increase of the number of MVBs where MHC II complexes accumulate. Given that human immunodeficiency virus recruits the MVB machinery for its assembly process, our data raise the possibility that Nef is involved in viral assembly through its effect on MVBs.

Animals↗
PubMed2005

Yos1p is a novel subunit of the Yip1p-Yif1p complex and is required for transport between the endoplasmic reticulum and the Golgi complex.

Yeast Yip1p is a member of a conserved family of transmembrane proteins that interact with Rab GTPases. Previous studies also have indicated a role for Yip1p in the biogenesis of endoplasmic reticulum (ER)-derived COPII transport vesicles. In this report, we describe the identification and characterization of the uncharacterized open reading frame YER074W-A as a novel multicopy suppressor of the thermosensitive yip1-4 strain. We have termed this gene Yip One Suppressor 1 (YOS1). Yos1p is essential for growth and for function of the secretory pathway; depletion or inactivation of Yos1p blocks transport between the ER and the Golgi complex. YOS1 encodes an integral membrane protein of 87 amino acids that is conserved in eukaryotes. Yos1p localizes to ER and Golgi membranes and is efficiently packaged into ER-derived COPII transport vesicles. Yos1p associates with Yip1p and Yif1p, indicating Yos1p is a novel subunit of the Yip1p-Yif1p complex.

Adaptor Proteins, Vesicular Transport↗
PubMed1975

Immune complexes in cancer: demonstration of complexes in mice bearing neuroblastomas.

Immune complexes occurred in a large proportion of mice with syngeneic neuroblastomas. Circulating immune complexes formed in all mice, whereas almost 50% had deposits of host IgG and complement in a granular pattern along the mesangia and basement membranes of the renal glomeruli. The bound IgG was eluted and recovered from the glomeruli and demonstrated immunologic specificity to neuroblastoma cell-surface antigens.

Animals↗
PubMed2006

Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay.

Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNA containing premature termination codons (PTCs). In mammalian cells, recognition of PTCs requires translation and depends on the presence on the mRNA with the splicing-dependent exon junction complex (EJC). While it is known that a key event in the triggering of NMD is phosphorylation of the trans-acting factor, Upf1, by SMG-1, the relationship between Upf1 phosphorylation and PTC recognition remains undetermined. Here we show that SMG-1 binds to the mRNA-associated components of the EJC, Upf2, Upf3b, eIF4A3, Magoh, and Y14. Further, we describe a novel complex that contains the NMD factors SMG-1 and Upf1, and the translation termination release factors eRF1 and eRF3 (SURF). Importantly, an association between SURF and the EJC is required for SMG-1-mediated Upf1 phosphorylation and NMD. Thus, the SMG-1-mediated phosphorylation of Upf1 occurs on the association of SURF with EJC, which provides the link between the EJC and recognition of PTCs and triggers NMD.

Codon, Nonsense↗
PubMed2005

DISTORTED3/SCAR2 is a putative arabidopsis WAVE complex subunit that activates the Arp2/3 complex and is required for epidermal morphogenesis.

In a plant cell, a subset of actin filaments function as a scaffold that positions the endomembrane system and acts as a substrate on which organelle motility occurs. Other actin filament arrays appear to be more dynamic and reorganize in response to growth signals and external cues. The distorted group of trichome morphology mutants provides powerful genetic tools to study the control of actin filament nucleation in the context of morphogenesis. In this article, we report that DISTORTED3 (DIS3) encodes a plant-specific SCAR/WAVE homolog. Null alleles of DIS3, like those of other Arabidopsis thaliana WAVE and Actin-Related Protein (ARP) 2/3 subunit genes, cause trichome distortion, defects in cell-cell adhesion, and reduced hypocotyl growth in etiolated seedlings. DIS3 efficiently activates the actin filament nucleation and branching activity of vertebrate Arp2/3 and functions within a WAVE-ARP2/3 pathway in vivo. DIS3 may assemble into a WAVE complex via a physical interaction with a highly diverged Arabidopsis Abi-1-like bridging protein. These results demonstrate the utility of the Arabidopsis trichome system to understand how the WAVE and ARP2/3 complexes translate signaling inputs into a coordinated morphogenetic response.

Actin-Related Protein 2↗
PubMed2005

Crystallization of mitochondrial respiratory complex II from chicken heart: a membrane-protein complex diffracting to 2.0 A.

A procedure is presented for preparation of diffraction-quality crystals of a vertebrate mitochondrial respiratory complex II. The crystals have the potential to diffract to at least 2.0 A with optimization of post-crystal-growth treatment and cryoprotection. This should allow determination of the structure of this important and medically relevant membrane-protein complex at near-atomic resolution and provide great detail of the mode of binding of substrates and inhibitors at the two substrate-binding sites.

Animals↗
PubMed1978

Viral immune complexes in systemic lupus erythematosus: C-type viral complex deposition in skin.

Punch biopsies were examined by indirect immunofluorescence for immune complex deposits containing C-type viral antigen. Antisera specific for immunoglobulins and HEL-12 virus mediated fluorescence at the dermal-epidermal junction and in vessel walls of 16 of 16 biopsies involved skin from patients with systemic lupus erythematosus (SLE). Preimmune sera did not mediate fluorescence and gradient purified HEL-12 virus, simian sarcoma virus and baboon endogenous virus but not Rous sarcoma virus blocked the reaction of anti-HEL-12 virus serum with SLE tissue. Ten biopsies from uninvolved skin of the patients with SLE did not react with the antiviral serum, nor did tissue from 9 patients with discoid lupus erythematosus, psoriasis, bullous pemphigoid or normal skin. These data support the hypothesis that C-type viral immune complexes participate in the pathogenesis of SLE.

Animals↗
PubMed1984

Phagocytosis by normal polymorphonuclear leukocytes of immune complexes from serum of patients with Felty's syndrome and rheumatoid arthritis with special reference to IgE immune complexes.

Sera from patients with Felty's syndrome, rheumatoid arthritis (RA) and controls were investigated for the presence of immune complexes (IC) using phagocytosis by normal polymorphonuclear leukocytes and direct immunofluorescence technique. IC visible as large cytoplasmic inclusions were seen in 19 of 24 cases of Felty's syndrome, 3 of 16 cases of RA, and all 3 patients with extraarticular manifestations, and none of 21 control sera. IC containing IgG, IgA and complement C3 were found in nearly all positive cases. IgM IC were found in only 8 of the Felty's syndrome cases, IgE in 5 and beta-2-microglobulin in one case, respectively. A tendency to increasing number of large inclusion positive cells in vitro was found inversely correlated to the number of circulating leukocytes in the Felty patients at the time of serum sampling. In contrast, small cytoplasmic inclusions were found both in Felty's syndrome and RA patients and in some of the controls, and IgG and C3 were the most frequent constituents in these cases. As these inclusions were found in all groups it may have little significance. IgE IC as determined by a PEG precipitation technique were positive in the same 5 cases of Felty's syndrome with IgE containing inclusions, and in one case of RA with extraarticular manifestations. The complexed IgE amounted to about 3% of the total serum concentration of IgE. Phagocytosed IC may be involved in the pathogenesis of neutropenia and contribute to the inflammatory processes in Felty's syndrome.

Adult↗
PubMed2003

Characterization of a novel origin recognition complex-like complex: implications for DNA recognition, cell cycle control, and locus-specific gene amplification.

The origin recognition complex (ORC) plays a central role in eukaryotic DNA replication. Here we describe a unique ORC-like complex in Tetrahymena thermophila, TIF4, which bound in an ATP-dependent manner to sequences required for cell cycle-controlled replication and gene amplification (ribosomal DNA [rDNA] type I elements). TIF4's mode of DNA recognition was distinct from that of other characterized ORCs, as it bound exclusively to single-stranded DNA. In contrast to yeast ORCs, TIF4 DNA binding activity was cell cycle regulated and peaked during S phase, coincident with the redistribution of the Orc2-related subunit, p69, from the cytoplasm to the macronucleus. Origin-binding activity and nuclear p69 immunoreactivity were further regulated during development, where they distinguished replicating from nonreplicating nuclei. Both activities were lost from germ line micronuclei following the programmed arrest of micronuclear replication. Replicating macronuclei stained with Orc2 antibodies throughout development in wild-type cells but failed to do so in the amplification-defective rmm11 mutant. Collectively, these findings indicate that the regulation of TIF4 is intimately tied to the cell cycle and developmentally programmed replication cycles. They further implicate TIF4 in rDNA gene amplification. As type I elements interact with other sequence-specific single-strand breaks (in vitro and in vivo), the dynamic interplay of Orc-like (TIF4) and non-ORC-like proteins with this replication determinant may provide a novel mechanism for regulation.

Animals↗
PubMed1976

Cryoprecipitates and immune complexes: differentiation between cold insoluble immune complexes and nonspecific cryoprecipitates.

Cold insoluble circulating immune complexes occurred in 77% of rabbits immunized with 125I BSA. 9.8% of the total cryoprotein was 125I BSA. This represented 43% of the serum antigen. Tripling the antigen concentration in vitro decreased the amount of cold insoluble antigen by as much as 83%. In nonspecific cryoprecipitates only 0.4% of the total cryoprotein was 125I BSA. This represented only 0.028% of the serum antigen. Tripling of the antigen concentration in vitro increased the amount of cold insoluble antigen. Cold insoluble circulating immune complexes occur at a critical antigen-antibody ratio and can be differentiated from nonspecific cryoprecipitates.

Animals↗
PubMed1979

Circulating immune complexes in acute uveitis: a possible association with the histocompatibility complex locus antigen B27.

39 patients with acute anterior uveitis were investigated for the presence of circulating immune complex (IC) and correlation with the major histocompatibility complex antigen B27 (HLA-B27). ICs were demonstrated by a number of techniques including rheumatoid factor, complement (C) activation, anticomplementary activity, cryoglobulins, inhibition of IgG-EA rosette formation and neutrophil chemotactic index (NCI) in plasma. ICs were most frequently detected in HLA-B27-negative patients. These results indicate that deposition of circulating ICs may be involved in the pathogenesis of acute anterior uveitis, especially in HLA-B27-negative patients.

Acute Disease↗