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At least 937 records · Page 52Linked to original sources
PubMed2005

Analysis of the role of Rab27 effector Slp4-a/Granuphilin-a in dense-core vesicle exocytosis.

Slp4-a/granuphilin-a is a member of the synaptotagmin-like protein (Slp) family and consists of an N-terminal Slp homology domain (SHD) and C-terminal tandem C2 domains. Slp4-a is specifically localized on secretory granules in some endocrine and exocrine cells through its SHD, and it attenuates Ca(2+)-dependent dense-core vesicle (DCV) exocytosis when transiently expressed in endocrine cells. Although the SHD of Slp4-a interacts with three distinct Rab species (Rab3A, Rab8A, and Rab27A) in vitro, in contrast to other Slp members, which only recognize Rab27 isoforms, Slp4-a functions as a Rab27A effector during DCV exocytosis under physiological conditions. This chapter describes various approaches that have been used to characterize the function of Slp4-a as a Rab27A effector, rather than a Rab3A or Rab8A effector, both in in vitro and in neuroendocrine PC12 cells. Specifically, the methods that have been used to analyze (1) the physical interaction between Slp4-a and Rab27A, including pull-down assay and cotransfection assay in COS-7 cells; (2) the localization of Slp4-a-Rab27A complex on DCVs in PC12 cells; and (3) the involvement of Slp4-a and Rab27A in DCV exocytosis by neuropeptide Y (NPY) cotransfection assay combined with site-directed mutagenesis are described.

Amino Acid Sequence↗
PubMed2006

The RIN family of Ras effectors.

The human RIN1 gene was first identified as a cDNA fragment that interfered with RAS-induced phenotypes in the yeast Saccharomyces cerevisiae. Subsequent analysis of full-length RIN1 clones showed that the protein product of this gene is a downstream effector of RAS and binds with high affinity and specificity to activated HRAS. Two downstream RIN1 effector pathways have been described. The first involves direct activation of RAB5-mediated endocytosis. The second involves direct activation of ABL tyrosine kinase activity. Importantly, each of these distinct RIN1 functions is enhanced by activated RAS, suggesting that RIN1 represents a unique class of RAS effector connected to two independent signaling pathways. In this chapter, we summarize our assays and approaches for evaluating the biochemistry and biology of RIN1.

Animals↗
PubMed2004

HIV-1 specific CD8+ T cells with an effector phenotype and control of viral replication.

Most people infected with HIV-1 cannot control viral replication despite the presence of virus-specific CD8+ T cells. It has been postulated that this inability is related to the failure of these cells to mature into fully differentiated effector cells. We tested this hypothesis by comparing the maturation phenotype of virus-specific CD8+ T cells in people who could control viral replication off anti-retroviral therapy with those who could not. In five patients with treated acute HIV-1-infection, structured treatment interruption (STI) induced control of viral replication was associated with expansion of virus-specific CD8+ T cells with a fully differentiated effector phenotype. These effector cells were also expanded in treatment-naive chronically infected individuals who spontaneously controlled viral replication, and augmented expression of perforin was noted in both settings. Our data show that full maturation of virus-specific CD8+ T cells is possible in the context of HIV-1-infection, and suggest that such maturation might be important in viral control.

Antiretroviral Therapy, Highly Active↗
PubMedDate not supplied

The influence of glycosylation on the thermal stability and effector function expression of human IgG1-Fc: properties of a series of truncated glycoforms.

Antibodies are multifunctional molecules that following the formation of antibody antigen complexes, may activate mechanisms to effect the clearance and destruction of the antigen (pathogen). The IgG molecule is comprised of three globular protein moieties (2Fab+Fc) linked through a flexible hinge region. While the Fabs bind antigens, the Fc triggers effector mechanisms through interactions with specific ligands, e.g. cellular receptors (FcgammaR), and the C1 component of complement. Glycosylation of IgG-Fc has been shown to be essential for efficient activation of FcgammaR and C1. We report the generation of a series of truncated glycoforms of IgG-Fc, and the analysis of the contribution of the residual oligosaccharide to IgG-Fc function and thermal stability. Differential scanning microcalorimetry has been used to compare the stabilities of the homogeneous glycoforms of IgG1-Fc. The results show that all truncated oligosaccharides confer a degree of functional activity, and thermodynamic stability to the IgG1-Fc, in comparison with deglycosylated IgG1-Fc. The same truncated glycoforms of an intact IgG1 anti-MHC Class II antibody are shown to exhibit differential functional activity for FcgammaRI and C1 ligands, relative to deglycosylated IgG1. The minimal glycoform investigated had a trisaccharide attached to each heavy chain and can be expected to influence protein structure primarily in the proximity of the N-terminal region of the C(H)2 domain, implicated as a binding site for multiple effector ligands. These data provide a thermodynamic rationale for the modulation of antibody effector functions by different glycoforms.

Calorimetry, Differential Scanning↗
PubMed2002

Nitric oxide as a regulatory and effector molecule in the immune system.

Nitric oxide (NO) as a small ubiquitous molecule influencing a great variety of biological processes in the organism. Within the immune system, increased levels of NO were observed in various immunopathological situations, inflammatory reactions and during the response to transplantation and tumour antigens. It appears that NO can influence various facets of immune response. We studied involvement and the role of NO in immune response to skin allograft in mice. The production of NO at the site of graft rejection correlated well with the kinetic of rejection reaction and with the fate of the allograft. Graft infiltrating macrophages were identified as a principal cell population producing NO and the production of NO by macrophages was dependent on the presence of activated CD4(+) T cells. Survival of skin allografts was significantly prolonged by the treatment of graft recipients with 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a specific inhibitor of inducible NO synthase (iNOS). These results suggest a role for NO as the effector cytotoxic molecule involved in the graft rejection. Experiments in vitro demonstrated that NO, in addition to its effector function, acts as a modulator of cytokine production. Spleen cells stimulated with alloantigens in the presence of AMT or S-ethylisothiourea (EIT), an another selective iNOS inhibitor, produced considerably more interleukin (IL)-4 and IL-10 than the cells stimulated in the absence of iNOS inhibitors. The production of Th1 cytokines IL-2 and interferon (IFN)-gamma was not enhanced by the inhibition of NO synthesis. The results altogether show that NO can act in transplantation reactions as an immunomodulator on cytokine production level and as an effector molecule involved in the graft destruction.

Animals↗
PubMed1999

Influence of different types of effectors on the kinetic parameters of suicide inactivation of catalase by hydrogen peroxide.

The effects of cyanide and azide ions (class A), sodium-n-dodecyl sulphate (SDS) and 2-mercaptoethanol (class B), 3-aminotriazole (class C) and NADPH (class D) on the initial activity (ai), inactivation rate constant (ki) and the partition ratio (r) of bovine liver catalase reaction with its suicide substrate, hydrogen peroxide, were studied in 50 mM sodium phosphate buffer, pH 7.0 at 27 degrees C. The above kinetic parameters were determined by processing the progress curve data. In class A, which contains fast and reversible inhibitors of catalase, a proportional decrease in ai and ki was observed by inhibitors, so that the r remained constant. In class B, which contains slow and irreversible inactivators, a decrease in ai and constancy of ki and r were observed when catalase was incubated in the presence of such inactivators for a determined time. In class C, containing effector which can combine with intermediate compound I, ai was relatively unchanged but an increase in ki and a decrease in r were observed. In class D, containing effector which reduces compound I to ferricatalase, ai was not affected significantly but some decrease in ki was detected which was linked with an increase in r. These results demonstrate that different classes of effectors affect the determined kinetic parameters of catalase in various ways. Thus, determination of such parameters by simple kinetic experiments can be carried out for classification of the agents which have an effect on the kinetics of catalase.

Animals↗
PubMed2001

Evolutionary expansion of CRIB-containing Cdc42 effector proteins.

Cdc42, a small GTPase, regulates actin polymerization and other signaling pathways through interaction with many different downstream effector proteins. Most of these effector proteins contain a Cdc42-binding domain, called a CRIB domain. Here, we describe the evolutionary analysis of these CRIB-containing proteins in yeast, worms, flies and humans. The number of CRIB-containing effector proteins increases from yeast to humans, involving both an increase within families and the emergence of new families. These evolutionary changes correlate with the development of the more complex signaling pathways present in higher organisms.

Animals↗
PubMed1982

Studies on in-vivo priming of the trinitrophenyl-reactive cytotoxic effector-system. III. Are helper T cells involved in the in-vitro generation of cross-reactive as well as restricted cytotoxic responses?

The present study investigates the role of helper cells from trinitrophenyl(TNP)-primed mice in the generation of cytotoxic T lymphocytes (CTL) which lyse TNP-modified syngeneic (TNP-self) targets and cross-reactively lyse TNP-allogeneic target cells. Anti-TNP CTL activities generated from primed (either by intraperitoneal injection of TNP-syngeneic cells or by skin painting with trinitrochlorobenzene) and unprimed spleen cells were compared. When effector populations with comparable lytic activities on TNP-self targets were tested against allogeneic TNP-modified targets, only the in vivo primed effector cells displayed significant cytotoxicity. Since radioresistant helper cells have been found to enhance the anti-TNP-self CTL response, the question was raised whether this helper population could be shown to be involved in the enhanced TNP-allogeneic cross-reactive lysis. Normal spleen cells co-cultured with radioresistant helper cells failed to induce any detectable lysis on TNP-allogeneic targets under conditions for which these helper cells did enhance the lysis detected on TNP-self targets. These results suggest that triggering of such TNP-cross-reactive effector cells during the in vivo priming stage is responsible for the in vitro generation of cross-reactivity.

Animals↗
PubMed1999

Cell-mediated immunity to Toxoplasma gondii: initiation, regulation and effector function.

Cell-mediated immune responses are essential for host control of intracellular infections. Toxoplasma gondii is a protozoan parasite that infects multiple vertebrate species and invades multiple cell types. Upon initial encounter with the immune system, the parasite rapidly induces production of the type-1 promoting cytokine IL-12 most likely from a subpopulation of dendritic cells. NK and T cells are then activated and triggered to synthesize IFN-gamma, the major mediator of host resistance during the acute and chronic phases of infection. During the acute phase, a concomitant IL-10 response dampens the systemic type-1 cytokine production and prevents lethal immunopathology. Cytokine (IFN-gamma und TNF-alpha) rather than cytotoxicity-based effector functions are more critical for protective immunity both during the acute and chronic phases of T. gondii infection. Both hemopoietic and non-hemopoietic cellular elements act as IFN-gamma and TNF-dependent effectors of host resistance. Type II iNOS-derived nitric oxide (NO) is required mainly for hemopoietic cell-derived effector cell activity in the central nervous system (CNS) during the chronic phase of infection. Nevertheless, in both the acute and chronic stages, IFN-gamma-dependent but iNOS-independent mechanism(s) play a major function in parasite control and their identification remains an important challenge for this field.

Acute Disease↗
PubMed1980

ADCC effector function in patients with atopic dermatitis. A possible mechanism of susceptibility to severe cutaneous viral infections.

Peripheral blood mononuclear cells from patients with chronic atopic dermatitis were evaluated as effectors of antibody-dependent cellular cytotoxicity (ADCC) to determine if faulty effector function might explain the susceptibility of atopics to severe cutaneous viral infections in spite of adequate specific antibody titers. Eleven atopic patients whose dermatitis was well controlled and who were not infected or on immunosuppressive therapy were studied using sensitized human and chicken erythrocyte targets at three different effector:target ratios. No significant differences in mean ADCC were seen between atopics and controls. However, the function of peripheral blood mononuclear cells from atopic patients who had a previous history of severe cutaneous viral infection was significantly depressed against sensitized chicken, but not human targets. This suggests that atopic patients who develop severe cutaneous viral infections may represent a subset of atopics with an intrinsic or variable defect in K lymphocyte--mediated ADCC which might render them susceptible to persistent, extensive viral infections.

Adult↗
PubMed2002

Heterotropic effectors control the hemoglobin function by interacting with its T and R states--a new view on the principle of allostery.

Careful analyses of precise oxygenation curves of hemoglobin (Hb) clearly indicate that, contrary to the common belief, allosteric effectors exert a dramatic control of the oxygenation characteristics of the protein by binding not only to the T (unligated), but also to the R (ligated) state, in a process that is proton-driven and involves proton uptake. The most striking functional changes were obtained when the allosteric effectors were bound to the fully ligated Hb: the oxygen affinity decreased dramatically, Bohr effect was enhanced, and cooperativity of oxygen ligation was almost absent, emulating a Root effect-like behavior. However, structural analysis, such as Cys beta 93 sulfhydryl reactivity and ultraviolet circular dichroism, confirmed that the ligated Hb was in fact in the R state, despite its extremely low affinity state features. These findings provide a new global view for allosteric interactions and invoke for a modern interpretation of the role of allosteric effectors and a reformulation of the Monod-Wyman-Changeaux model for control of allosteric systems, and other complementary models as well.

Adult↗
PubMed1999

Quantifying elasticity analysis: how external effectors cause changes to metabolic systems.

The sites of action of external effectors, such as inhibitors or hormones, on metabolic systems can be described qualitatively by elasticity analysis, or quantitatively by regulation analysis. The use of the latter approach has been limited, due to its practical complexity. In this study, we report mathematical relationships that relate the finite changes in system variables (fluxes and metabolite concentrations) to changes in activity of metabolic processes brought about by a single step addition of an effector. The activation or inhibition of a process by an effector is measured from changes in flux and intermediate levels. The changes in activity of each process can be used to describe, semi-quantitatively, which activations or inhibitions of the system processes are important in bringing about the observed levels of system variables.

Elasticity↗
PubMed2003

Cytokine-driven proliferation and differentiation of human naïve, central memory and effector memory CD4+ T cells.

Memory T lymphocytes divide in vivo in the absence of antigen maintaining a pool of central memory (T(CM)) and effector memory cells (T(EM)) with distinct effector function and homing capacity. We compared human CD4+ naïve T, T(CM) and T(EM) cells for their capacity to proliferate in response to cytokines, which have been implicated in T cell homeostasis. Interleukin (IL)-7 and IL-15 expanded with very high efficiency T(EM), while T(CM) were less responsive and naïve T cells did not respond at all. Dendritic cell (DC)-derived cytokines allowed naïve T cells to respond selectively to IL-4 and potently boosted the response of T(CM) to IL-7 and IL-15 by increasing the expression of the IL-2/IL-15Rss and the common gamma chain (gamma(c)). The ERK and the p38 MAP kinases were selectively required for TCR and cytokine-driven proliferation, respectively. Importantly, in cytokine-driven cultures T(CM) proliferated and some of the proliferating cells acquired effector function and non-lymphoid tissue homing capacity. Ex vivo BrdU incorporation experiments showed that both T(CM) and T(EM) proliferated under steady state conditions in vivo. Altogether these results provide a plausible mechanism for the maintenance of a polyclonal and functionally diverse repertoire of human CD4+ memory T cells and for a sustained antigen-independent generation of T(EM) from a pool of T(CM) cells.

Animals↗
PubMed2003

Quantitative structure-activity relationship (QSAR) analysis of aromatic effector specificity in NtrC-like transcriptional activators from aromatic oxidizing bacteria.

A quantitative structure-activity relationship (QSAR) approach was taken to provide mechanistic insights into the interaction between the chemical structure of inducing compounds and the transcriptional activation of aromatic monooxygenase operons among the XylR/DmpR subclass of bacterial NtrC-like transcriptional regulators. Compared to XylR and DmpR, a broader spectrum of effector compounds was observed for the TbuT system from Ralstonia pickettii PKO1. The results of QSAR analysis for TbuT suggested that a steric effect, rather than hydrophobic or electronic effects, may be the predominant factor in determining aromatic effector specificity, and the active site of the regulator may positively interact not only with the methyl moiety but also with the most electron-rich aryl side of an aromatic effector.

Bacterial Proteins↗
PubMed2003

Role of ICAM-1 and P-selectin expression in the development and effector function of CD4+CD25+regulatory T cells.

Dynamic regulatory mechanisms prevent autoreactive T cell activation. Upon T cell receptor crosslinking, CD4+CD25+ T regulatory (T(R)) cells block both the proliferation and cytokine production of CD4+CD25- effector cells in an apparent antigen non-specific manner. Within the T(R)population, L-selectin (CD62L)(hi)T(R)cells have been described as more efficient suppressors of T cell proliferation than CD62L(low)T(R)cells. We have previously reported that CD4+CD25+CD62L(hi)T(R)cells express elevated levels of two additional adhesion molecules, ICAM-1 (CD54) and P-selectin (CD62P) in comparison to non-T(R)cells. In the current study, we investigated the functional contribution of CD54 and CD62P expression to the suppressive phenotype of T(R)cells both in vitro and in vivo. While the CD4+CD25+ T(R)cell population was demonstrated to be significantly larger in CD62P-/- mice than in wild-type C57BL/6 mice, CD62P-/- T(R)cell function was deficient in vitro, but not in vivo. Interestingly, we detected no deficiencies in T(R)cell numbers or effector function in CD54-/- mice suggesting that T(R)cells may differ from effector CD4+ T cells in the requirement for CD54 expression within the immunological synapse. Collectively, these findings indicate that CD62P may influence T(R)cell differentiation/development and that T(R)cell activation occurs independently of CD54 expression.

Adoptive Transfer↗
PubMed1997

G proteins, effectors and GAPs: structure and mechanism.

G proteins from a diverse family of regulatory GTPases which, in the GTP-bound state, bind to and activate downstream effectors. Structures of Ras homologs bound to effector domains have revealed mechanisms by which G proteins couple GTP binding to effector activation and achieve specificity. Complexes between structurally unrelated GTPase-activating proteins with complementary G proteins suggest common mechanisms by which GTP hydrolysis is stimulated via direct interactions with conformationally labile switch regions of the G protein.

Binding Sites↗
PubMed1998

Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following overexpression of haem oxygenase (HSP 32).

This is the first report on suppression of immune effector functions following upregulation of heat shock protein 32 (HSP 32), known as haem oxygenase (HO-1). Here we evaluated the effect of cobalt-protoporphyrin (CoPP)-induced HO-1 expression on cell-mediated immune responses. Administration of CoPP to CBA mice resulted in overexpression of HO-1 in the spleen, liver and kidneys. In vitro measurements of T cell-mediated and NK-cell-mediated cytotoxicity in spleens from CoPP-treated animals demonstrated a severe suppression of their effector functions while administration of Zn-PP or vitamin B12 had no effect. Furthermore, CoPP therapy decreased the lymphoproliferative alloresponse and differentiation of cytotoxic T cells. Inhibition of proliferation appeared to be due to cell growth arrest with an increased number of cells staying in G0/G1 phase. Despite the suppressed proliferative response, IL-2 production in the MLR was not inhibited. In contrast, CoPP decreased the production of IL-10, IFN-gamma and TNF-alpha. In vivo, CoPP prolonged the survival of heterotopic heart allografts in mice. The immunosuppressive effects following CoPP-mediated upregulation of HO-1 were similar to those observed after peptide-mediated upregulation of HO-1. The results indicate that overexpression of HO results in the inhibition of several immune effector functions and thus provides an explanation for stress-induced immunosuppression.

Animals↗
PubMed2000

IP-10 is critical for effector T cell trafficking and host survival in Toxoplasma gondii infection.

The generation of an adaptive immune response against intracellular pathogens requires the recruitment of effector T cells to sites of infection. Here we show that the chemokine IP-10, a specific chemoattractant for activated T cells, controls this process in mice naturally infected with Toxoplasma gondii. Neutralization of IP-10 in infected mice inhibited the massive influx of T cells into tissues and impaired antigen-specific T cell effector functions. This resulted in >1000-fold increase in tissue parasite burden and a marked increase in mortality compared to control antibody-treated mice. These observations suggest that IP-10 may play a broader role in the localization and function of effector T cells at sites of Th1 inflammation.

Animals↗