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PubMed1992

An explanation for the defect in secretion of IgM Mott cells and their predominant occurrence in the Ly-1 B cell compartment.

Mott cells are a variant form of plasma cell in which the immunoglobulin (Ig), rather than being secreted, accumulates in rough endoplasmic reticulum-derived vesicles called Russell bodies. We have examined the molecular cause of this defect and the in vivo origin of IgM Mott cells. Our examination of the Ig variable region gene sequences of two IgM Mott hybridomas derived from C.B-20 Ly-1 B cells showed all to be germ line. In a series of mix and match transfection experiments, the Mott phenotype was only reconstituted when the original Mott specificity was expressed as an IgM, suggesting that both the specificity and the isotype were critical to the formation of Russell bodies. Based on our finding that Russell body formation was dependent on the Ig isotype being IgM, we suggest that the Mott phenotype is apparent only after differentiation of B cells into plasma cells and that probably the major cause of the IgM Mott phenotype is low-affinity interaction of the Mott Ig with some as yet unknown intracellular component(s) being stabilized by the intrinsic high avidity of the pentameric secreted form of IgM. Consistent with this proposal was the finding that after in vitro lipopolysaccharide (LPS) stimulation of sorted Ly-1 B cells derived from C.B-20 mice, Mott cells represented up to 5% of the IgM plasma cells in the culture. LPS stimulation of conventional B cells also induced the appearance of IgM Mott cells, but at the much reduced level of 0.1%, suggesting that the major, if not the only, source of Mott cells in vivo is the Ly-1 B cell population. A possible causal relationship between the elevated frequency of Mott cells in the Ly-1 B cell-derived LPS blasts and the repertoire selection inherent in the development of these B cells is discussed.

Amino Acid Sequence↗
PubMed2004

SsrA tagging of Escherichia coli SecM at its translation arrest sequence.

SecM is expressed from the secM-secA operon and activates the expression of secA in response to secretion defects. The 3'-end of secM encodes an "arrest sequence," which can interact with the ribosomal exit tunnel, preventing complete secM translation under secretion-defective conditions. In a cis-acting manner, ribosome stalling enhances secA translation. Pro(166) is the last residue incorporated when SecM elongation is arrested. We report that secretion deficiencies lead to SsrA tagging of SecM after Pro(166), Gly(165), and likely Arg(163). Northern blot analysis revealed the presence of a truncated secM transcript, likely issued from a secM-secA cleavage. The level of secM transcripts was decreased either when secM translation was totally prevented or when Pro(166) was mutated. However, the accumulation of a truncated secM transcript required secM translation and was prevented when the SecM arrest sequence was inactivated by a point mutation changing Pro(166) to Ala. We suggest that ribosome pausing at the site encoding the arrest sequence is required for formation of the truncated secM mRNA. SsrA tagging affected neither the presence of the secM mRNA nor secA expression, even under translocation-defective conditions. It is therefore likely that SsrA tagging of SecM occurs only after cleavage of secM-secA mRNA within the secM open reading frame encoding the SecM arrest sequence. Accumulation of transcripts expressing arrested SecM generated growth inhibition that was alleviated by the SsrA tagging system. Therefore, SsrA tagging of SecM would rescue ribosomes to avoid excessive jamming of the translation apparatus on stop-less secM mRNA.

Adenosine Triphosphatases↗
PubMed2001

Disulfide bond formation in secreton component PulK provides a possible explanation for the role of DsbA in pullulanase secretion.

When expressed in Escherichia coli, the 15 Klebsiella oxytoca pul genes that encode the so-called Pul secreton or type II secretion machinery promote pullulanase secretion and the assembly of one of the secreton components, PulG, into pili. Besides these pul genes, efficient pullulanase secretion also requires the host dsbA gene, encoding a periplasmic disulfide oxidoreductase, independently of disulfide bond formation in pullulanase itself. Two secreton components, the secretin pilot protein PulS and the minor pseudopilin PulK, were each shown to posses an intramolecular disulfide bond whose formation was catalyzed by DsbA. PulS was apparently destabilized by the absence of its disulfide bond, whereas PulK stability was not dramatically affected either by a dsbA mutation or by the removal of one of its cysteines. The pullulanase secretion defect in a dsbA mutant was rectified by overproduction of PulK, indicating reduced disulfide bond formation in PulK as the major cause of the secretion defect under the conditions tested (in which PulS is probably present in considerable excess of requirements). PulG pilus formation was independent of DsbA, probably because PulK is not needed for piliation.

Bacterial Outer Membrane Proteins↗
PubMed2005

Molecular analysis of a novel hereditary C3 deficiency with systemic lupus erythematosus.

A case of inherited homozygous complement C3 deficiency (C3D) in a patient with systemic lupus erythematosus (SLE) and the molecular basis for this deficiency are reported. A 22-year-old Japanese male was diagnosed as having SLE and his medical history revealed recurrent tonsillitis and pneumonia. He was diagnosed as having C3D because of undetectable serum C3 level. His parents were consanguineous. Sequence analysis of C3D cDNA revealed a homozygous deletion of exon 39 (84bp). A single base substitution (AG to GG) in the 3'-splice acceptor site of intron 38 was identified by sequencing the genomic DNA. Expression of C3Delta(ex39) cDNA, the C3cDNA lacking exon 39, in COS-7 cells revealed that C3Delta(ex39) was retained in endoplasmic reticulum-Golgi intermediate compartment because of defective secretion. These data indicate that a novel AG-->GG 3'-splice acceptor site mutation in intron 38 caused aberrant splicing of exon 39, resulting in defective secretion of C3.

Adult↗
PubMed2002

Genetic and phenotypic variability between families with hereditary protein S deficiency.

While many mutations thought to result in protein S (PS) deficiency are known, there have been few attempts to relate genotype expression with plasma phenotype. We have investigated the nature and consequence of PS gene (PROS1) mutations in 17 PS-deficient families who presented with mixed type I and type III phenotypes. Seven different mutations were found in nine families: delG-34 (STOP codon at -24), Val-24Glu, Arg49Cys, Asn217Ser, Gly295Val, +5 G to A intron j and His623Pro. PS wild type (PSWT) and the five missense mutants were transiently expressed in COS-1 cells. All mutants expressed lower (p<0.05) PS antigen compared to PSWT (100%). The mutants Val-24Glu, Gly295Val and His623Pro expressed very low/undetectable PS levels. The mutant Asn217Ser produced around 30% of PSWT, while the mutant Arg49Cys had the highest PS levels (around 50%). Metabolic labelling and pulse-chase experiments showed that all of the mutants had impaired secretion, but this was of variable severity. Also, enhanced intracellular degradation of unsecreted material was found for all mutants. There was a strong correspondence between plasma free PS levels in carriers of the mutations, secreted PS from transfected COS-1 cells and labelled PS from 24 h conditioned medium in pulse-chase experiment. We conclude that the magnitude of secretion defect depends on the nature of the PROS1 mutation and influences the level of free PS in plasma. It is likely that the severity of the secretion defect will determine the risk for venous thrombosis.

Amino Acid Substitution↗
PubMed1998

Inefficient assembly and intracellular accumulation of antibodies with mutations in V(H) CDR2.

We previously described secretion defects in four mutants of the murine anti-phosphocholine Ab, T15. The mutant heavy (H) chains had amino acid replacements in the V(H) complementarity-determining region 2 (HCDR2) and were expressed at normal intracellular levels. Here, the intracellular fate of the secretion-defective mutant heavy chains was investigated. Metabolic labeling demonstrated that the T15 wild-type Ab was secreted within a 4-h chase. In contrast, the mutant H chains accumulated with intracellular t(1/2) values ranging from 10 to 24 h. The mutant H chains were associated with increased levels of the molecular chaperones BiP and GRP94, and remained endoglycosidase H sensitive, suggesting retention in the endoplasmic reticulum. Assembly of the mutant H chains with T15 light (L) chain was arrested at the H2 and H2L intermediate stages of the T15 wild-type pathway (H2 --> H2L --> H2L2). Even though some assembly with L chain occurred, it was not as a secretion-competent H2L2 Ig moiety. The T15 L chains coexpressed with mutant H chains were degraded efficiently except for a minor L chain population with a long t(1/2) that was apparently protected at the H2L stage. To our knowledge, this is the first study demonstrating that intracellular half-lives of Ig H and L chains can be influenced by somatic mutations in HCDR2.

Animals↗
PubMed1992

Neurotransmitter-induced hypothalamic-pituitary-adrenal axis responsiveness is defective in inflammatory disease-susceptible Lewis rats: in vivo and in vitro studies suggesting globally defective hypothalamic secretion of corticotropin-releasing hormone.

The susceptibility of female Lewis (LEW/N) rats to the development of streptococcal cell wall (SCW)-induced arthritis and other autoimmune phenomena is associated with the inability of their hypothalamic-pituitary-adrenal (HPA) axis to adequately respond to inflammatory stimuli. In contrast, resistance to the development of SCW-induced arthritis and other inflammatory autoimmune manifestations in histocompatible female Fischer rats (F344/N) is related to their intact HPA axis response to inflammatory mediators. To evaluate the mechanism and the specificity of the HPA axis defect in LEW/N rats, we examined the ability of three major excitatory neurotransmitter systems to activate the HPA axis in both Lewis and Fisher rats. The responsiveness of plasma ACTH and corticosterone to the cholinergic muscarinic receptor agonist arecoline, the alpha 1-adrenergic receptor agonist methoxamine and the serotonin (5-HT) type 2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane were significantly blunted and/or abolished in LEW/N compared to F344/N rats. To localize the HPA axis defect to the hypothalamic CRH neuron, we evaluated the ability of explanted hypothalami from the two strains to secrete immunoreactive CRH in vitro, in response to acetylcholine (ACh), norepinephrine (NE), 5-HT and the 5-HT agonist quipazine. LEW/N hypothalami released less immunoreactive CRH (iCRH) in response to ACh, NE, 5-HT and quipazine than F344/N hypothalami. The dose-response curves of these compounds in the former were shifted to the right and/or abolished, suggesting decreased sensitivity of LEW/N hypothalami to these neurotransmitters.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1996

Alterations in calcium channel currents underlie defective insulin secretion in a transgenic mouse.

A transgenic mouse overexpressing a mutant form of calmodulin (CaM-8) that is selectively targeted to pancreatic beta-cells has an impaired ability to secrete insulin in response to elevated blood glucose. Fluorescence measurements of cytosolic Ca2+ concentration ([Ca2+]i) showed that intracellular Ca2+ rises produced by glucose were smaller than normal in beta-cells of CaM-8 mice. Glucose utilization rates were not different between the CaM-8 and control beta-cells, suggesting that glucose metabolism was unperturbed by CaM-8. Ion channel defects were implicated in the phenotype of CaM-8 beta-cells because treatment of these cells with tolbutamide, a blocker of ATP-sensitive K+ channels, produced smaller than normal amounts of insulin secretion and Ca2+ rises. Depolarization with elevated extracellular K+ also produced smaller Ca2+ rises in beta-cells from CaM-8 mice. Whole-cell patch-clamp recordings revealed that Ca2+ channel currents of beta-cells from CaM-8 mice were half as large as Ca2+ currents in control cells, while the currents carried by delayed rectifier and ATP-sensitive K+ channels were similar in magnitude in both cell types. We conclude that expression of the CaM-8 form of calmodulin causes a down-regulation of Ca2+ channel currents, which reduces Ca2+ entry and accumulation when glucose stimulates closure of the ATP-sensitive K+ channels. The reduction in intracellular Ca2+ accumulation then prevents an adequate amount of insulin from being secreted from beta-cells of CaM-8 mice.

Adenosine Triphosphate↗
PubMed2006

C-terminal amino acid alteration rather than late termination causes complete deficiency of thyroxine-binding globulin CD-NeuIsenburg.

CONTEXT: T(4)-binding globulin (TBG) is the main transport protein for T(4) in blood and a member of the superfamily of serine proteinase inhibitors. So far, 14 mutations leading to familial complete TBG deficiency have been reported. Eleven of these are caused by mutations leading to truncation of the molecule, and three are caused by single amino acid substitutions. OBJECTIVE: We report and study the complete deficiency TBG variant found in a patient from NeuIsenburg, Germany (TBG-CDNI). METHODS: Direct DNA sequencing was used to identify the TBG-CDNI mutation in the propositus, which was confirmed by allele-specific amplification. Site-directed mutagenesis and expression in Xenopus oocytes was used to study the secretion defect of TBG-CDNI and several variants by Western blot and T(4)-binding assay. RESULTS: The deletion of two nucleotides in codon 384 (1211_1212delTC) causes a frameshift altering the last 11 residues, introduces a new glycosylation site, and elongates the molecule by seven new amino acids. In contrast to normal TBG, TBG-CDNI was not secreted by Xenopus oocytes. Elongation of normal TBG by seven alanines did not affect its secretion or binding properties. On the other hand, neither disruption of its new glycosylation site nor termination of TBG-CDNI at the normal length repaired its secretion defect. CONCLUSIONS: In this first late termination variant of complete TBG deficiency, alteration of beta-strand 5B, located in the core of the molecule, rather than elongation of the molecule or introduction of a new glycosylation site, suffices to disrupt secretion of TBG-CDNI.

Adult↗
PubMed1994

Molecular mechanism of kininogen deficiency in brown Norway Katholiek rats.

1. The Brown Norway (B/N) Katholiek rat is a mutant strain of plasma kininogen deficiency. The plasma of B/N-Katholiek rats was shown to contain only 3-5% of high-molecular-weight and low-molecular-weight kininogens (HK and LK) of the normal level by specific RIA, and 30% of prekallikrein was detected by amidase activity. However, HK antigen in the liver microsomal fraction of B/N-Katholiek rats was about 60% of that of normal rats. 2. In this paper we compare and discuss synthesis and secretion of HK and LK by primary cultures of livers of deficient and normal rats. The deficient hepatocytes could synthesize HK and LK in the same way as normal cells but could not secrete mature forms of HK and LK in the medium. Examination of the subcellular localization of the mutant HK in the hepatocytes showed that a larger amount of mutant HK antigen, compared to normal rats, was found in the 10,000 g fraction, which is rich in lysosomes, suggesting that the mutant HK may be transported to the lysosomes. 3. We also analyzed sequence of the HK cDNA of B/N-Katholiek and B/N-Kitasato rats and found a point mutation of G to A at nucleotide 487, which locates at the heavy chain region of HK and LK. 4. We constructed five expression plasmids to transfect COS-1 cells to examine HK secretion. COS-1 cells transfected with the plasmids containing the G to A transition could not secrete and retained HK, while those cells transfected with the plasmids containing normal G released HK into the medium. 5. These results indicate that a point mutation G to A at nucleotide 487, resulting in an amino acid transition from alanine (163) to threonine, is responsible for the defective secretion of HK and LK by the liver of B/N-Katholiek rats. We also discuss other cases of secretion defect of plasma proteins reported in the literature.

Animals↗
PubMed1992

Marfan syndrome: defective synthesis, secretion, and extracellular matrix formation of fibrillin by cultured dermal fibroblasts.

We studied the synthesis, secretion, and aggregation into the extracellular matrix of fibrillin by dermal fibroblasts from 26 probands with the Marfan syndrome. Cells from seven probands synthesized approximately half the normal amount of fibrillin when compared with intrafamilial or unrelated controls. Cells from an additional seven probands synthesized a normal amount of fibrillin but secreted the protein less efficiently than control cells. Cells from a further eight probands synthesized and secreted normal amounts of fibrillin but the protein was poorly incorporated into extracellular matrix. Cells from the remaining four probands were indistinguishable from control cells in their synthesis and processing of fibrillin. Cells from 18 family members of 10 of the probands were also studied. Cells from affected individuals in the same family had the same biochemical defect and those from unaffected family members were indistinguishable from controls. These results indicate that mutations in the gene that encodes fibrillin are responsible for the Marfan syndrome in the majority of individuals (confirming recent immunohistochemical and genetic linkage studies) and that a variety of mutations can produce the phenotype associated with the syndrome.

Adolescent↗
PubMed1993

Brefeldin A causes a defect in secretion in Saccharomyces cerevisiae.

Brefeldin A (BFA) blocks secretion in mammalian cells and causes the redistribution of Golgi resident membrane proteins to the endoplasmic reticulum (Klausner, R. D., Donaldson, J. G., and Lippincott-Schwartz, J. (1992) J. Cell Biol. 116, 1071-1080). The target(s) of BFA and its mechanism of action remain unknown. The yeast Saccharomyces cerevisiae represents an ideal organism in which to identify the BFA targets, since many molecules essential for vesicular traffic have been already identified taking advantage of the powerful genetics of this system. Unfortunately, wild type S. cerevisiae strains are largely insensitive to BFA (Hayashi, T., Takatsuki, A., and Tamura, G. (1982) Agric. Biol. Chem. 46, 2241-2248). Here we demonstrate that an erg6 mutant (Gaber, R., Copple, D., Kennedy, B., Vidal, M., and Bard, M. (1989) Mol. Cell. Biol. 9, 3447-3456) defective in the biosynthesis of ergosterol is sensitive to BFA. Treatment of erg6 cells with BFA results in an arrest in growth and causes a block in secretion similar to that seen in mammalian cells treated with BFA. Our data suggest that the changes in the erg6 strain allows BFA entry and that this strain can be used to examine the molecular mechanism of BFA action.

Antifungal Agents↗
PubMed1996

Empty sellae, impaired testosterone secretion, and defective hypothalamic-pituitary growth and gonadal axes in children with Bardet-Biedl syndrome.

We evaluated growth parameters and hypothalamic-pituitary-gonadal and growth functions in five children with Bardet-Biedl syndrome (BBS). Three of the five children had stature below the fifth percentile for age. Their growth hormone (GH) response to provocation was defective, and computed tomographic (CT) scanning revealed empty sellae in all of them. All the children were obese (body mass index [BMI] > 95th percentile for age). Three had hypercholesterolemia. Their basal serum testosterone concentration and testosterone response to 3-day human chorionic gonadotropin (HCG) stimulation were significantly lower than the levels in 12 age-matched obese normal children. Testosterone secretion failed to respond to HCG therapy for 4 weeks. Both basal gonadotropin levels (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and gonadotropin responses to LH-releasing hormone (LHRH) stimulation were normal and did not differ among the two study groups. It appears that primary hypogonadism is a cardinal feature of BBS, and it may be accompanied by hypothalamic and pituitary abnormalities.

Adolescent↗
PubMed2003

Acute pancreatitis, expression of inducible nitric oxide synthase and defective insulin secretion.

A high level of nitric oxide (NO) produced by inducible NO synthase (iNOS) is involved in pancreatic beta-cell dysfunction and apoptosis. In the present study, we examined whether iNOS is also expressed in beta cells after induction of acute pancreatitis (AP) in the rat. Pancreatic islets taken from AP animals and incubated for 60 min in the presence of 20.0 mmol/l glucose showed a decreased insulin secretory response to glucose. The basal insulin release at 1.0 mmol/l glucose was also moderately reduced. Experiments on the dynamics of insulin secretion from perfused pancreas revealed an impairment of both first and second phase of glucose-stimulated insulin release after the induction of AP. Confocal microscopy demonstrated that most of the beta cells in pancreas of rat with AP expressed strong immunoreactivity for iNOS. This was further confirmed by biochemical and Western blot analysis that showed a marked increase in iNOS protein expression and enzyme activity concomitant with a modest reduction in the cNOS protein and activity. Although the mechanisms underlying the defective insulin secretory response of beta cells seen during the early stage of AP are complex, the present finding suggests that the expression of iNOS and a marked iNOS-derived NO production in the beta cells may play at least a contributory role in the impairment of beta-cell function.

Acute Disease↗
PubMed1989

Severe T lymphocyte immunodeficiency associated with hypogammaglobulinemia: defective lymphokine secretion but enhanced autologous mixed lymphocyte reaction.

The multiparameter immunologic study of T cells of a patient with acquired hypogammaglobulinemia was investigated, since he had a normal B-cell number and function. His peripheral blood lymphocytes were found to contain predominant CD4+ CD45R+ T cells with a clear deficiency of CD4+ CDw29+ as well as CD8+ T cells. His T cells proliferated in response to phytohemagglutinin (PHA) and pokeweed mitogen (PWM), but no immunoglobulin was secreted in PWM-induced patient's T-cell and normal B-cell differentiations. His T cells were also found to possess concanavalin A (Con A)-induced suppressor function when cocultured with normal T cells, as well as IgG-, IgA-, and IgM-specific suppressor function on PWM-induced normal T- and B-cell differentiations. The patient's T cells were found to secrete elevated amounts of interleukin-2 but failed to secrete two important B-cell stimulating factors, B-cell growth factor and B-cell differentiation factor, in response to PHA. An investigation of immunoregulatory T-cell function in the autologous mixed lymphocyte reaction (AMLR) and allogeneic mixed lymphocyte reaction (MLR) indicated that the patient's T cells produced an enhanced AMLR but were deficient in MLR. These results suggest that the abnormalities we have identified in this patient with hypogammaglobulinemia reflect an intrinsic defect of T cells in the humoral immune response to produce three major immunoglobulins.

Agammaglobulinemia↗
PubMed1996

Cellular basis for protein C deficiency caused by a single amino acid substitution at Arg15 in the gamma-carboxyglutamic acid domain.

Protein C is a zymogen of an anticoagulant vitamin K-dependent serine protease. Inherited protein C deficiency is often associated with a high risk for venous thromboembolism. It is characteristic of protein C deficiency that most single amino acid replacements result in type I (secretion defect) deficiency. To determine the molecular and cellular bases of protein C deficiency, we expressed recombinant human protein C mutants in which Arg15 was mutated to either Gly, Trp, Gln, Leu, or Pro by a single base exchange. Arg15 is one of the conservative residues in the gamma-carboxyglutamic acid (Gla) domains of the vitamin K-dependent coagulation factors, and is also one of the high frequency multiple mutation sites in protein C deficiency. In transient expression studies using human kidney 293 cells, the relative amounts of Arg15 mutants secreted into the medium and determined by enzyme-linked immunosorbent assay (ELISA) were as follows: Gly, 42%; Trp, 14%; Gln, 54%; Leu, 22%; and Pro, 13%, the amount of wild-type (Wt) protein C being taken as 100%. Thus, the order of the secreted amounts of the recombinant mutants was determined to be Wt > Gln > Gly > Leu > Trp, Pro. Pulse-chase experiments using both transiently-transfected and a pool of stably-transfected 293 cells, and stably-transfected BHK cells showed the same order of secretion efficiency. Since this order correlated well with that of the hydrophobicity scale of amino acid side chains, a conformational alteration of the Gla domain resulting in impaired secretion may be dependent on the hydrophobicity of the replaced amino acid. In transient cells, the relative radioactivities of pulse-labeled bands of all recombinant protein C were almost equal, suggesting that the same translational efficiency for Wt and all Arg15 mutants. All of the Arg15-mutated protein C precursors were shown to be located in the same organelle as protein disulfide isomerase (PDI), an endoplasmic reticulum-resident protein, and were sensitive to endoglycosidase H digestion. These results suggest that mutations of the highly conserved Arg15 in the Gla domain of protein C caused a secretion defect to variable degrees depending on replaced amino acid residue.

Amino Acid Sequence↗
PubMed1993

Selective protein degradation in the yeast exocytic pathway.

Protein degradation in the exocytic pathway was studied in Saccharomyces cerevisiae using human alpha-1-protease inhibitor (A1Pi) as a reporter molecule. Yeast cells transformed with A1Pi cDNA genes synthesized A1Pi that entered the secretion pathway and accumulated in the endoplasmic reticulum (ER). Cells expressing A1PiM (wild-type) accumulated about 10-fold more A1Pi than cells expressing A1PiZ (secretion defective variant). Analyses of A1Pi mRNA indicated that the low level of A1PiZ relative to A1PiM was not the result of differential gene transcription. Pulse-chase A1Pi radiolabeling showed that A1PiM and A1PiZ were degraded at different rates and suggested a rapid specific turnover of newly synthesized A1PiZ in the ER. Accumulated A1Pi was degraded at comparable rates in both wild-type cells and cells deficient in vacuolar protease activity, indicating that degradation of A1Pi did not occur in the vacuole. Studies to investigate the intracellular location of the degradative process, using temperature-sensitive secretion defective yeast strains, suggested the possibility that degradation occurs not only in the ER but at a second site accessed by vesicle transport. Together, these results demonstrate that a selective protein degradation process operates early in the yeast cell exocytic pathway.

Cloning, Molecular↗