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PubMed1983

Plasma membrane expansion terminates in Saccharomyces cerevisiae secretion-defective mutants while phospholipid synthesis continues.

Phospholipid synthesis activity and plasma membrane growth have been studied in the Saccharomyces cerevisiae temperature-sensitive, secretion-defective mutants isolated by Novick and Schekman (Proc. Natl. Acad. Sci. U.S.A. 76:1858-1862, 1979; Novick et al., Cell 21:205-215, 1980). The mutants, sec1 through sec23, do not grow at 37 degrees C and exhibit lower rates of phospholipid synthesis than does the wild-type strain X2180. None of the mutants exhibits a decline in lipid synthesis rapid enough to explain secretion failure. Plasma membrane growth was assessed indirectly by examining the osmotic sensitivity of spheroplasts derived from cultures transferred from 24 to 37 degrees C. Spheroplasts from the normal-growing strain X2180 exhibited a small rapid increase in osmotic sensitivity and stabilized at a more sensitive state. Spheroplasts from the sec mutants exposed to the same temperature shift exhibited progressively increasing osmotic sensitivity. Cycloheximide treatment prevented progressive increases in osmotic fragility. These data are compatible with the hypothesis that plasma membrane expansion is restricted in the sec mutants. During incubation at 37 degrees C, the accumulation of intracellular materials within the no-longer expanding plasma membrane exerts osmotic stress on the membrane, increasing with time. The gene products defective in Novick and Schekman's sec mutants appear to be required for both extracellular protein secretion and plasma membrane growth in yeast cells.

Cell Membrane↗
PubMed1984

Platelet-activating factor is a weak platelet agonist: evidence from normal human platelets and platelets with congenital secretion defects.

We have examined the effects of a novel platelet agonist, platelet activating factor (PAF), on human platelets. Irreversible aggregation and 14C-serotonin secretion in response to PAF (10(-5) M) was found to be dependent on both thromboxane production and secreted adenosine diphosphate (ADP). Liberation of arachidonic acid (AA) from membrane-bound phospholipids is a prerequisite step in platelet thromboxane production. Studies with 3H-AA-labeled platelets revealed that PAF (10(-5) M) was a weak stimulus for the mobilization of AA. In addition, PAF (10(-5) M) was found to be a weak inducer of thromboxane synthesis (mean = 6 pmol/10(8) platelets) as compared to thrombin 5 U/ml (mean = 177 pmol/10(8) platelets), measured using a radioimmunoassay for thromboxane B2. Formation of phosphatidic acid is an early step in stimulus-response coupling in platelets. Our studies indicate that PAF is a weak stimulus for phosphatidic acid formation as well. To obtain further insights into its action, we examined the effect of PAF on platelets from three groups of patients with congenital secretion defects: patients with the storage pool deficiency, those with impaired thromboxane synthesis due to impaired liberation of AA from phospholipids, and those with impaired secretion despite normal granule stores and thromboxane production. The response to PAF was impaired in all patients, providing further evidence that PAF-induced platelet activation is dependent on secreted ADP and thromboxane A2 synthesis, and occurs by mechanisms common to a number of agonists. Overall, these studies indicate that PAF is a weak platelet agonist.

Adenosine↗
PubMed1989

Interleukin 2 and soluble interleukin 2-receptor secretion defect in vitro in newly diagnosed type I diabetic patients.

In this study, we investigated whether an interleukin 2 (IL-2) secretion defect by peripheral blood mononuclear cells (PBMCs) after in vitro stimulation with phytohemagglutinin (PHA-M) occurs in either newly diagnosed or long-standing type I (insulin-dependent) diabetic patients and whether it is accompanied by a dysregulation of soluble IL-2-receptor (IL-2RS) production. PBMC cultures (2.5 x 10(6) cells), unstimulated or stimulated with PHA-M (25 micrograms/ml), from 20 type I diabetic patients (10 with time since onset less than 3 mo and 10 with long-term diabetes of less than 3 yr) and 10 control subjects were studied for the production of IL-2 and IL-2RS in their respective supernatants. No difference was found in IL-2 production in unstimulated cultures of type I patients compared with control subjects, although a significant decrease from PHA-M-stimulated cultures were seen (newly diagnosed, 1.7 +/- 0.3 ng/2.5 x 10(6) cells; long-standing, 2.2 +/- 0.3 ng/2.5 x 10(6) cells; P less than .001 and P less than .05, respectively) compared with control subjects (3.6 +/- 0.4 ng/2.5 x 10(6) cells). In regard to the production of IL-2RS, no difference exists for unstimulated cultures, whereas, after PHA-M stimulation, both newly diagnosed and long-term-diabetic patients showed a decrease in the IL-2RS levels (318 +/- 50 and 331 +/- 62 U/2.5 x 10(6) cells; P less than .02 and P less than .05, respectively) compared with normal subjects (463 +/- 34.2 U/2.5 x 10(6) cells). Thymus-activated cell phenotypes confirmed the T-lymphocyte activation after a 48-h culture period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2004

Reduction of SNAP25 in acid secretion defect of Foxl1-/- gastric parietal cells.

Foxl1 is a winged helix transcription factor expressed in the mesenchyme of the gastrointestinal tract. In the absence of Foxl1, parietal cells fail to secrete gastric acid in response to various secretagogue stimuli including cAMP. A marked decrease in H+,K(+)-ATPase expression was observed even though a substantial number of parietal cells still existed in Foxl1-deficient mice. Ultrastructural analysis suggested that the gastric acid secretion defect in Foxl1-deficient mice is mainly due to impairment in the fusion of cytoplasmic tubulovesicular structures to the apical canalicular plasma membrane. Among the molecules involved in the membrane fusion event, only SNAP25 showed a significant decrease in mRNA expression, which likely caused the impairment in acid secretion from parietal cells in Foxl1-deficient mice, with the reduction in H+,K(+)-ATPase expression contributing to additional effect.

Animals↗
PubMed1984

Platelet secretion defect in patients with the attention deficit disorder and easy bruising.

Platelet function was evaluated in 12 patients with the attention deficit disorder and lifelong history of easy bruising. Aggregation and 14C-serotonin secretion studies in platelet-rich plasma in response to adenosine diphosphate (ADP), epinephrine, and arachidonic acid did not reveal striking abnormalities. Secretion of adenosine triphosphate (ATP), ADP, beta-hexosaminidase, and beta-glucuronidase by gel-filtered platelets in response to the divalent cation ionophore A23187 and low concentrations of thrombin (less than or equal to 0.1 U/ml) was impaired in patients as compared to normals. The aggregation response to A23187 (4 microM) was absent in 8 of the 12 patients. The total stores of the secretable constituents, the retention of incorporated 14C-serotonin, and the arachidonate metabolism of the platelets were normal. Our findings suggest a new platelet disorder with impaired secretion mechanism, without storage pool deficiency or impaired arachidonate metabolism. The secretion defect in platelets represents a tissue disorder in a functional psychiatric disease. We refocus attention on the role of platelets as a model for neurons in functional disorders, with emphasis on secretion mechanisms rather than amine uptake, storage, and metabolism.

Adolescent↗
PubMed1988

Repair of the secretion defect in the Z form of alpha 1-antitrypsin by addition of a second mutation.

Homozygous inheritance of the Z-type mutant form of the alpha 1-antitrypsin (alpha 1AT) gene results in the most common form of alpha 1AT deficiency, a human hereditary disease associated with a high risk for the development of emphysema and an increased incidence of neonatal hepatitis. The alpha 1AT-synthesizing cells of individuals with the Z gene have normal alpha 1AT messenger RNA levels, but alpha 1AT secretion is markedly reduced secondary to accumulation of newly synthesized alpha 1AT in the rough endoplasmic reticulum. Crystallographic analysis of alpha 1AT predicts that in normal alpha 1AT, a negatively charged Glu342 is adjacent to positively charged Lys290. Thus the Glu342----Lys342 Z mutation caused the loss of a normal salt bridge, resulting in the intracellular aggregation of the Z molecule. The prediction was made that a second mutation in the alpha 1AT genet that changed the positively charged Lys290 to a negatively charged Glu290 would correct the secretion defect. When the second mutation was added to the Z-type complementary DNA, the resulting gene directed the synthesis and secretion of amounts of alpha 1AT similar to that directed by the normal alpha 1AT complementary DNA in an in vitro eukaryotic expression system. This suggests the possibility that a human hereditary disease can be corrected by inserting an additional mutation in the same gene.

Animals↗
PubMed1986

Suppression of growth and protein secretion defects in Escherichia coli secA mutants by decreasing protein synthesis.

We devised a new selection for conditionally lethal suppressors of secA mutants. This selection allows the isolation of both temperature-sensitive and cold-sensitive suppressor mutations, whereas previous studies were limited to nonlethal or cold-sensitive suppressor mutations. Two temperature-sensitive suppressor mutations lie in genes required for protein synthesis: asnS, the gene for the asparaginyl-tRNA synthetase, and divE, which encodes the tRNASer1. A previously characterized mutation in alaS, the gene for the alanyl-tRNA synthetase, suppresses the growth and secretion defects of a secA mutant. Although the primary effects of these suppressor mutations are different, it is likely that they cause suppression of secA mutations by altering the rate of protein synthesis, since the protein synthesis inhibitors, chloramphenicol and tetracycline, also suppress secA mutations. Chloramphenicol also suppresses the growth defect of certain other sec mutants. We postulate that the impaired secretory capacity of sec mutants can be offset by decreasing the rate of elongation of secreted proteins or by decreasing the total amount of secreted proteins per cell. The results indicate that our initial goal to identify cellular secretory components as suppressors of secA mutations might be difficult to achieve because of a high frequency of nonspecific suppressors that alter protein synthesis. Unexpectedly, the suppressor approach provides a direct genetic selection for mutants in protein synthesis.

Bacterial Proteins↗
PubMed2000

Repression of ribosome and tRNA synthesis in secretion-defective cells is signaled by a novel branch of the cell integrity pathway.

The transcription of ribosomal DNA, ribosomal protein (RP) genes, and 5S and tRNA genes by RNA polymerases (Pols) I, II, and III, respectively, is rapidly and coordinately repressed upon interruption of the secretory pathway in Saccharomyces cerevisiae. We find that repression of ribosome and tRNA synthesis in secretion-defective cells involves activation of the cell integrity pathway. Transcriptional repression requires the upstream components of this pathway, including the Wsc family of putative plasma membrane sensors and protein kinase C (PKC), but not the downstream Bck1-Mkk1/2-Slt2 mitogen-activated protein kinase cascade. These findings reveal a novel PKC effector pathway that controls more than 85% of nuclear transcription. It is proposed that the coordination of ribosome and tRNA synthesis with cell growth may be achieved, in part, by monitoring the turgor pressure of the cell.

DNA-Binding Proteins↗
PubMed1982

Secretion defect in platelets stored at 4 degrees C.

To understand the functional changes induced by storage, we have examined the adenine nucleotides of platelets stored for 72 hr at 22 degrees C and 4 degrees C. Ten platelet concentrates (PC) were stored at each temperature with five in each group having a final volume of 50 ml and 30 ml. The total ATP and ADP content of platelets decreased following storage in all 4 groups of PC, with the decrease being greater in the PC stored at 22 degrees C than those at 4 degrees C. The mean thrombin secretable ATP + ADP content of platelets from PC stored at 22 degrees C and 4 degrees C were 29.7% and 19.7% of the total content, respectively (p less than 0.001). Thus, cold stored platelets have a higher total content of ATP + ADP but secrete distinctly lesser amounts than 22 degrees C stored platelets. Labeling of the metabolic pool adenylates with 14C-adenine revealed a greater decrease in the adenylate energy charge of the platelets stored at 4 degrees C. The secretion defect demonstrated in cold stored platelets may be related to the inability of these platelets to maintain ATP homeostasis.

Adenosine Diphosphate↗
PubMed2001

The CFTR-mediated protein secretion defect: pharmacological correction.

The cystic fibrosis transmembrane conductance regulator (CFTR) mediates secretion of mucins and serous proteins. The aim was to correct pharmacologically the CFTR defect in protein secretion in airway gland cells and so to correct the viscous mucous secretions in cystic fibrosis (CF) airways and lungs. The strategies tested included direct activation of CFTR, bypass of CFTR-mediated protein secretion and movement of the mutated form of CFTR (DeltaF(508)-CFTR) to the cell membrane. Compounds related to 3-isobutyl-1-methylxanthine (IBMX), including a selective type-IV phosphodiesterase inhibitor and the adenosine receptor antagonists 8-cyclopentyltheophylline (CPT) and 8-cyclopentyl-1,3-dipropylxanthine (CPX), corrected the defective beta-adrenergic stimulation of mucin secretion in CFTR antibody-inhibited submandibular gland cells. CPT also corrected lactoferrin secretion in DeltaF(508)/DeltaF(508)-CFTR nasal gland cells. The data suggest that correction of CFTR protein secretion activity is not mediated by excessive increase in cyclic AMP, involves direct interaction with CFTR but does not require increase in CFTR Cl(-) channel activity. Regulated glycoprotein secretion was characterised in the airway gland cell line Calu-3 to investigate whether a CFTR bypass is present. Studies of DeltaF(508)-CFTR trafficking using confocal imaging showed that some DeltaF(508)-CFTR colocalised with the apical membrane protein CD59; however a large amount was mislocalised within the cell. The results showing pharmacological correction of the defective CFTR-mediated protein secretion afford promise for the development of a rational drug therapy for CF patients.

Adrenergic beta-Agonists↗
PubMed1987

X-linked hypogammaglobulinaemia with a late secretion defect. A family study.

Three boy cousins suffering from x-linked hypogammaglobulinaemia have been described. Their disease is quite different from the classical x-linked hypogammaglobulinaemia. We present data from 15 family members of three families. The three mothers are sisters and 3 boys from 5 are suffering from immunodeficiency. HLA A, B and DR typing and in vitro diagnostics of immune functions of all family members were carried out. In the patients we could demonstrate a well functioning T cell system which seems to be regular for T cell help on PMW driven B cell maturation into cytoplasmic immunoglobulin positive (cIg+) cells of all immunoglobulin classes but we had no evidence for IgG secreting cells in a plaque forming cell (PFC) assay. The registration of spontaneous suppressor phenomena should be taken into account. If patients undergo an gamma-globulin therapy the changed suppressor effects come back to normal values but the secretion defect is unchanged. The three healthy mothers express one identical haplotype (A2 B8 DR3) which we could demonstrate in the three patients but also in one healthy boy.

Agammaglobulinemia↗
PubMed1997

Homologous recombination partly restores the secretion defect of underglycosylated acid phosphatase in yeast.

The majority of secreted acid phosphatase in Saccharomyces cerevisiae is encoded by the PH05 gene. The secretion level of this acid phosphatase is directly determined by its level of glycosylation. Consequently, PHO5-11-encoded acid phosphatase which lacks 11 of 12 glycosylation sites is only poorly secreted. We have isolated and characterized both UV- and EMS-induced variants, which are partly able to restore the secretion of acid phosphatase. Our data indicate that the improved secretion is caused by mitotic intrachromosomal recombination between the PHO5-11 allele and the homologous tandemly repeated PHO3 sequences, resulting in the restoration of glycosylation sites in PHO5-11. Two different recombination mechanisms, unequal sister-chromatid exchange and sister-chromatid gene conversion, are responsible for these alterations of the PHO5-11 locus. Thus, recombination between mutant and wild-type sequences are able to restore the ability of mutant yeast cells to secrete acid phosphatase.

Acid Phosphatase↗
PubMed2002

Apoptosis in the beta cells: cause or consequence of insulin secretion defect in diabetes?

Pancreatic beta-cell dysfunction and insulin resistance are two interrelated defects in the pathophysiology of type 2 diabetes. Defects in peripheral insulin action precede the development of glucose intolerance, as the pancreas compensates for insulin resistance by increasing insulin production and secretion. This may be achieved by enhancing cellular secretory capacity or by increasing beta-cell mass. Over time, the pancreatic secretion of insulin becomes inadequate for the extent of insulin resistance, and the levels of fasting and postprandial glucose rise leading to the onset of frank hyperglycemia, which leads to reduction in beta-cell function and survival through a process referred to as glucose toxicity. There is increasing evidence that apoptosis is the main mode of pancreatic beta-cell death not only in type 1 but also in type 2 diabetes. Recently, studies in knockout mice, human and rat islets, and pancreatic beta-cell lines demonstrated that defective insulin signaling in beta-cells might play an important pathophysiological role by affecting both secretory function and cell survival. The purpose of this review is to present recent advances in understanding of the interrelationship between molecular mechanisms underlying defects in insulin secretion and beta-cell survival in type 2 diabetes caused by impaired activation of insulin signaling pathways.

Animals↗
PubMed1986

The interleukin 2 secretion defect in vitro in systemic lupus erythematosus is reversible in rested cultured T cells.

Interleukin 2 (IL 2) secretion in response to mitogenic stimulation in vitro is strongly reduced in circulating T lymphocytes from patients with SLE. It is still not clear how this abnormality relates to the B cell hyperactivity in the disease. Some investigators proposed that an intrinsic T helper cell defect could lead to suppressor cell dysfunction and autoimmunity. Others have found that in fact increased suppressor cell activity can cause IL 2 hyposecretion. In the present study we report that the IL 2 secretion in response to PHA plus PMA by T cells from patients with SLE, which initially was decreased by a factor of 10 as compared with the IL 2 secretion in blood donor T cells, was restored when the T cells were rested for 2 to 3 days in culture before stimulation. IL 2 hyposecretion in SLE T cells and the kinetics of normalization in culture were not changed by the addition of normal adherent cells during the stimulation with PHA/PMA, occurred in the absence of significant cell death or proliferation or change of the T4:T8 cell ratio during the resting culture, were not due to a maturation of immature T6-positive cells (less than 1.5% T6 cells in SLE T cells), and also occurred in T8-depleted T4 cells alone. Furthermore, a normalization of IL 2 secretion took place in the presence of either SLE serum or normal serum, and the addition of fresh autologous T cells to 3-day-cultured SLE T cells did not cause suppression of IL 2 secretion. These data show that some rapidly reversible defect occurs in circulating T helper cells in SLE. That this could reflect an exhaustion of T helper cells that have been activated in vivo is discussed.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1996

Interferon-gamma secretion defects in haemophilia A patients receiving highly purified plasma-derived or recombinant factor VIII.

The outcome of developing immune responses is influenced by interactions among a large and complex network of secreted cytokines. T-cell secretion of interferon-gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha) and TNF-beta, or lymphotoxin contributes to the development of cell-mediated immunity, whereas secretion of interleukin (IL)-4, IL-5 and IL-6 contributes to development of humoral immunity. Humoral immunity to factor VIII (FVIII) develops in approximately 25% of severe haemophilia A patients. The aim of our research was to understand the underlying immune response to FVIII in patients with FVIII inhibitors. We report a defect in IFN-gamma secretion by peripheral blood mononuclear cells (PBMC) derived from haemophilia A patients, which was accompanied by a low level of mitogen-induced proliferation and a significant decrease in the percentage of natural killer (NK) cells. All of the observed defects were found in haemophilia A patients, both with and without FVIII inhibitors, who were free of viral infection and had been treated predominantly or exclusively with monoclonal antibody-purified or recombinant FVIII.

Child, Preschool↗
PubMed2000

Overproduction of the secretin OutD suppresses the secretion defect of an Erwinia chrysanthemi outB mutant.

OutB is a component of the Erwinia chrysanthemi Out secretion machinery. Homologues of OutB have been described in two other bacteria, Klebsiella oxytoca and Aeromonas hydrophila, but their requirement in the secretion process seems to be different. Study of OutB topology with the BlaM topology probe suggests that it is an inner-membrane protein with a large periplasmic domain. However, fractionation experiments indicate that it could be associated with the outer membrane through its C-terminal part. The secretion deficiency of an Erw. chrysanthemi outB mutant can be reversed by the addition of an inducer of the kdgR regulon. It was shown that this effect results from the increased expression of the secretin OutD and that secretion can be restored in an outB mutant by introducing the outD gene on a plasmid. Several experiments suggest an interaction between OutB and OutD. In Erw. chrysanthemi, the presence of OutD stabilizes OutB. OutD expressed in Escherichia coli can be protected from proteolytic degradation by the coexpression of OutB. This effect does not require the N-terminal, transmembrane segment of outB. OutB can be cross-linked with OutD by formaldehyde. These results indicate that OutB could act with OutD in the functioning of the Out secretion machinery.

Amino Acid Sequence↗
PubMed1996

Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families.

Non-insulin dependent diabetes mellitus (NIDDM) affects more than 100 million people worldwide and is associated with severe metabolic defects, including peripheral insulin resistance, elevated hepatic glucose production, and inappropriate insulin secretion. Family studies point to a major genetic component, but specific susceptibility genes have not yet been identified-except for rare early-onset forms with monogenic or mitochondrial inheritance. We have screened over 4,000 individuals from a population isolate in western Finland, identified 26 families (comprising 217 individuals) enriched for NIDDM and performed a genome-wide scan using non-parametric linkage analysis. We found no significant evidence for linkage when the families were analysed together, but strong evidence for linkage when families were classified according to mean insulin levels in affecteds (in oral glucose tolerance tests). Specifically, families with the lowest insulin levels showed linkage (P = 2 x 10(-6)) to chromosome 12 near D12S1349. Interestingly, this region contains the gene causing the rare, dominant, early-onset form of diabetes MODY3. Unlike MODY3 families, the Finnish families with low insulin have an age-of-onset typical for NIDDM (mean = 58 years). We infer the existence of a gene NIDDM2 causing NIDDM associated with low insulin secretion, and suggest that NIDDM2 and MODY3 may represent different alleles of the same gene.

Adult↗
PubMed1995

Age-related thymus involution: zinc reverses in vitro the thymulin secretion defect.

The inevitability of thymic involution in aging has been opened to question by two recent findings. First, it has been demonstrated that the synthesis and/or secretion of one thymic factor, zinc-thymulin (Zn-FTS), is still present, although reduced, in humans over 90 yr of age and in mice over 24 months of age. The major defect resides in the zinc saturation of thymulin, rather than in the synthesis and secretion rate of the polypeptide by the thymus. Zinc pool is in fact reduced in old age. Thymic explants from old mice in vitro for a short period (6 h) produce nearly the same amount of thymulin as young thymuses, but the zinc-bound form is nearly absent. Zinc addition to the cultures fully recovers the defect. These findings clearly suggest that thymic involution is not an intrinsic and irreversible phenomenon, but is largely due to microenvironmental factors, among which zinc is crucial.

Aging↗