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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of cell biology, 25 January 2010, Vol.188(2), pp.271-85
    Description: Nogo-A is one of the most potent myelin-associated inhibitors for axonal growth, regeneration, and plasticity in the adult central nervous system. The Nogo-A-specific fragment NogoDelta20 induces growth cone collapse, and inhibits neurite outgrowth and cell spreading by activating RhoA. Here, we show that NogoDelta20 is internalized into neuronal cells by a Pincher- and rac-dependent, but clathrin- and dynamin-independent, mechanism. Pincher-mediated macroendocytosis results in the formation of NogoDelta20-containing signalosomes that direct RhoA activation and growth cone collapse. In compartmentalized chamber cultures, NogoDelta20 is endocytosed into neurites and retrogradely transported to the cell bodies of dorsal root ganglion neurons, triggering RhoA activation en route and decreasing phosphorylated cAMP response element binding levels in cell bodies. Thus, Pincher-dependent macroendocytosis leads to the formation of Nogo-A signaling endosomes, which act both within growth cones and after retrograde transport in the cell body to negatively regulate the neuronal growth program.
    Keywords: Endosomes -- Metabolism ; Ganglia, Spinal -- Embryology ; Growth Cones -- Metabolism ; Myelin Proteins -- Metabolism ; Nerve Tissue Proteins -- Metabolism
    ISSN: 00219525
    E-ISSN: 1540-8140
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  • 2
    Language: English
    In: Neuroscience Letters, 03 August 2016, Vol.627, pp.168-177
    Description: In the adult retina, we have previously shown that Nogo-A was highly expressed in Müller glia. However, the role of Nogo-A in the glial cell physiology is not clear. In this study, we investigated the possible influence that Nogo-A may exert on other polarized molecules in Müller cells, in particular inwardly rectifying potassium channel 4.1 (Kir4.1) and aquaporin 4 (AQP4) that respectively control potassium and water exchange in glial cells. Our results showed that adenovirus-mediated Nogo-A overexpression with AdNogo-A increased the immunofluorescent signal of Kir4.1 in rat Müller cell line 1 (rMC-1) cells but did not change its expression level by Western blotting. , AdNogo-A induced ectopic Kir4.1 immunoreactivity throughout the radial processes of Müller cells compared with AdLacZ control virus. Surprisingly, AdNogo-A did not modify the distribution of Dp71 and AQP4 that are common binding partners for Kir4.1 in the dystrophin-associated protein (DAP) complex anchored at the plasma membrane of Müller glia. Immunoprecipitation experiments revealed molecular interactions between Nogo-A and Kir4.1. In Nogo-A KO mouse retinae, the distribution of Kir4.1 was not different from that observed in Wild-Type (WT) animals. In addition, potassium conductance did not change in freshly dissociated Nogo-A KO Müller glia compared with WT cells. In summary, the increase of Nogo-A expression can selectively influence the distribution of Kir4.1 in glia but is not essential for Kir4.1-mediated potassium conductance at the plasma membrane in physiological conditions. Nogo-A-Kir4.1 interactions may, however, contribute to pathological processes taking place in the retina, for instance, after ischemia.
    Keywords: Müller Cells ; Glia ; Retina ; Nogo-A ; Kir4.1 ; Medicine ; Anatomy & Physiology
    ISSN: 0304-3940
    E-ISSN: 1872-7972
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  • 3
    Language: English
    In: The Journal of infectious diseases, 15 June 2011, Vol.203(12), pp.1859-65
    Description: Haemophilus ducreyi 35000HP contains a homolog of the CpxRA 2-component signal transduction system, which controls the cell envelope stress response system in other gram-negative bacteria and regulates some important H. ducreyi virulence factors. A H. ducreyi cpxR mutant was compared with its parent for virulence in the human challenge model of experimental chancroid. The pustule formation rate in 5 volunteers was 33% (95% confidence interval [CI], 1.3%-65.3%) at 15 parent sites and 40% (95% CI, 18.1%-61.9%) at 15 mutant sites (P = .35). Thus, the cpxR mutant was not attenuated for virulence. Inactivation of the H. ducreyi cpxR gene did not reduce the ability of this mutant to express certain proven virulence factors, including the DsrA serum resistance protein and the LspA2 protein, which inhibits phagocytosis. These results expand our understanding of the involvement of the CpxRA system in regulating virulence expression in H. ducreyi.
    Keywords: Bacterial Proteins -- Genetics ; Chancroid -- Microbiology ; Haemophilus Ducreyi -- Genetics
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 4
    Language: English
    In: Infection and immunity, November 2013, Vol.81(11), pp.4160-70
    Description: Expression of the lspB-lspA2 operon encoding a virulence-related two-partner secretion system in Haemophilus ducreyi 35000HP is directly regulated by the CpxRA regulatory system (M. Labandeira-Rey, J. R. Mock, and E. J. Hansen, Infect. Immun. 77:3402-3411, 2009). In the present study, we show that this secretion system is also regulated by the small nucleoid-associated protein Fis. Inactivation of the H. ducreyi fis gene resulted in a reduction in expression of both the H. ducreyi LspB and LspA2 proteins. DNA microarray experiments showed that a H. ducreyi fis deletion mutant exhibited altered expression levels of genes encoding other important H. ducreyi virulence factors, including DsrA and Flp1, suggesting a possible global role for Fis in the control of virulence in this obligate human pathogen. While the H. ducreyi Fis protein has a high degree of sequence and structural similarity to the Fis proteins of other bacteria, its temporal pattern of expression was very different from that of enterobacterial Fis proteins. The use of a lacZ-based transcriptional reporter provided evidence which indicated that the H. ducreyi Fis homolog is a positive regulator of gyrB, a gene that is negatively regulated by Fis in enteric bacteria. Taken together, the Fis protein expression data and the observed regulatory effects of Fis in H. ducreyi suggest that this small DNA binding protein has a regulatory role in H. ducreyi which may differ in substantial ways from that of other Fis proteins.
    Keywords: Gene Expression Regulation, Bacterial ; Operon ; Bacterial Outer Membrane Proteins -- Biosynthesis ; Bacterial Proteins -- Biosynthesis ; Factor For Inversion Stimulation Protein -- Metabolism ; Haemophilus Ducreyi -- Genetics
    ISSN: 00199567
    E-ISSN: 1098-5522
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  • 5
    In: Proceedings of the National Academy of Sciences of the United States, Dec 5, 2000, Vol.97(25), p.13790
    Description: The effects of poliovirus 3A protein expression and poliovirus infection on the presentation of hepatitis C virus antigens in cultured chimpanzee cells were examined. Expression of poliovirus 3A protein inhibits protein secretion when expressed in isolation and was sufficient to protect chimpanzee cells from lysis by hepatitis C virus-specific cytotoxic T cells in standard [sup.51]Cr-release assays. Poliovirus infection also inhibited antigen presentation, as determined by decreased cytotoxic T cell activation. A mutation in 3A that abrogates the inhibition of protein secretion also abolished the effects of poliovirus on antigen presentation. These results demonstrate that the inhibition of secretion observed in poliovirus-infected cells substantially reduces the presentation of new antigens on the cell surface. These observations may reflect a general mechanism by which nonenveloped viruses such as poliovirus and other viruses that do not require a functional protein secretory apparatus can evade detection by the cellular immune response.
    Keywords: Polioviruses -- Research ; Hepatitis C Virus -- Research ; T Cells -- Research
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 6
    In: The Journal of Virology, 2001, Vol. 75(17), p.8158
    Description: During viral infections, the host secretory pathway is crucial for both innate and acquired immune responses. For example, the export of most proinflammatory and antiviral cytokines, which recruit lymphocytes and initiate antiviral defenses, requires traffic through the host secretory pathway. To investigate potential effects of the known inhibition of cellular protein secretion during poliovirus infection on pathogenesis, cytokine secretion from cells infected with wild-type virus and with 3A-2, a mutant virus carrying an insertion in viral protein 3A which renders the virus defective in the inhibition of protein secretion, was tested. We show here that cells infected with 3A-2 mutant virus secrete greater amounts of cytokines interleukin-6 (IL-6), IL-8, and beta interferon than cells infected with wild-type poliovirus. Increased cytokine secretion from the mutant-infected cells can be attributed to the reduced inhibition of host protein secretion, because no significant differences between 3A-2- and wild-type-infected cells were observed in the inhibition of viral growth, host cell translation, or the ability of wild-type- or 3A-2-infected cells to support the transcriptional induction of beta interferon mRNA. We surmise that the wild-type function of 3A in inhibiting ER-to-Golgi traffic is not required for viral replication in tissue culture but, by altering the amount of secreted cytokines, could have substantial effects on pathogenesis within an infected host. The global inhibition of protein secretion by poliovirus may reflect a general mechanism by which pathogens that do not require a functional protein secretory apparatus can reduce the native immune response and inflammation associated with infection.
    Keywords: Poliovirus ; Poliovirus ; Interleukin 6 ; Interleukin 8 ; Inflammation ; Cytokines ; Interleukin 6 ; Interleukin 8 ; ^a-Interferon ; Immune Response ; B-Interferon ; Protein 3a ; Viral Protein 3a ; Immune Response & Immune Mechanisms ; Viruses ; Other Cytokines (Tnf, Gm-Csf) ; Man ; Beta -Interferon ; Man ; Protein 3a ; Viral Protein 3a;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 7
    Language: English
    In: mBio, 20 May 2014, Vol.5(3), pp.e01178-14
    Description: Haemophilus ducreyi causes chancroid, a sexually transmitted infection. A primary means by which this pathogen causes disease involves eluding phagocytosis; however, the molecular basis for this escape mechanism has been poorly understood. Here, we report that the LspA virulence factors of H. ducreyi inhibit phagocytosis by stimulating the catalytic activity of C-terminal Src kinase (Csk), which itself inhibits Src family protein tyrosine kinases (SFKs) that promote phagocytosis. Inhibitory activity could be localized to a 37-kDa domain (designated YL2) of the 456-kDa LspA1 protein. The YL2 domain impaired ingestion of IgG-opsonized targets and decreased levels of active SFKs when expressed in mammalian cells. YL2 contains tyrosine residues in two EPIYG motifs that are phosphorylated in mammalian cells. These tyrosine residues were essential for YL2-based inhibition of phagocytosis. Csk was identified as the predominant mammalian protein interacting with YL2, and a dominant-negative Csk rescued phagocytosis in the presence of YL2. Purified Csk phosphorylated the tyrosines in the YL2 EPIYG motifs. Phosphorylated YL2 increased Csk catalytic activity, resulting in positive feedback, such that YL2 can be phosphorylated by the same kinase that it activates. Finally, we found that the Helicobacter pylori CagA protein also inhibited phagocytosis in a Csk-dependent manner, raising the possibility that this may be a general mechanism among diverse bacteria. Harnessing Csk to subvert the Fcγ receptor (FcγR)-mediated phagocytic pathway represents a new bacterial mechanism for circumventing a crucial component of the innate immune response and may potentially affect other SFK-involved cellular pathways. Phagocytosis is a critical component of the immune system that enables pathogens to be contained and cleared. A number of bacterial pathogens have developed specific strategies to either physically evade phagocytosis or block the intracellular signaling required for phagocytic activity. Haemophilus ducreyi, a sexually transmitted pathogen, secretes a 4,153-amino-acid (aa) protein (LspA1) that effectively inhibits FcγR-mediated phagocytic activity. In this study, we show that a 294-aa domain within this bacterial protein binds to C-terminal Src kinase (Csk) and stimulates its catalytic activity, resulting in a significant attenuation of Src kinase activity and consequent inhibition of phagocytosis. The ability to inhibit phagocytosis via Csk is not unique to H. ducreyi, because we found that the Helicobacter pylori CagA protein also inhibits phagocytosis in a Csk-dependent manner. Harnessing Csk to subvert the FcγR-mediated phagocytic pathway represents a new bacterial effector mechanism for circumventing the innate immune response.
    Keywords: Phagocytosis ; Bacterial Proteins -- Immunology ; Chancroid -- Enzymology ; Haemophilus Ducreyi -- Immunology ; Src-Family Kinases -- Immunology
    E-ISSN: 2150-7511
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  • 8
    Language: English
    In: The Journal of biological chemistry, 01 April 2005, Vol.280(13), pp.12494-502
    Description: Nogo-A, -B, and -C are generated from the Nogo/RTN-4 gene and share a highly conserved C-terminal domain. They lack an N-terminal signal sequence and are predominantly localized to the endoplasmic reticulum (ER). We found the N terminus of endogenous Nogo-A exposed on the surface of fibroblasts, DRG neurons, and myoblasts. Surface-expressed Nogo-A was also present on presynaptic terminals of the neuromuscular junction and on DRG neurons in vivo. Surface biotinylations confirmed the presence of all Nogo isoforms on the surface. To search for proteins that interact with Nogo-A and suggest a function for the large intracellular pool of Nogo-A, immunoprecipitations were performed. Surprisingly, the most predominant proteins that interact with Nogo-A are Nogo-B and Nogo-C as seen with radiolabeled lysates and as confirmed by Western blotting in multiple cell lines. Nogo-A, -B, and -C share a 180-amino acid C-terminal domain with two highly conserved hydrophobic stretches that could form a channel or transporter in the ER and/or on the cell surface.
    Keywords: Myelin Proteins -- Biosynthesis
    ISSN: 0021-9258
    E-ISSN: 1083351X
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  • 9
    Language: English
    In: 2014, Vol.12(1), p.e1001763
    Description: This study identifies a GPCR, S1PR2, as a receptor for the Nogo-A-Δ20 domain of the membrane protein Nogo-A, which inhibits neuronal growth and synaptic plasticity. ; Nogo-A is a membrane protein of the central nervous system (CNS) restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) as a Nogo-A-Δ20-specific receptor. Nogo-A-Δ20 binds S1PR2 on sites distinct from the pocket of the sphingolipid sphingosine 1-phosphate (S1P) and signals via the G protein G, the Rho GEF LARG, and RhoA. Deleting or blocking S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth and cell spreading. Blockade of S1PR2 strongly enhances long-term potentiation (LTP) in the hippocampus of wild-type but not Nogo-A mice, indicating a repressor function of the Nogo-A/S1PR2 axis in synaptic plasticity. A similar increase in LTP was also observed in the motor cortex after S1PR2 blockade. We propose a novel signaling model in which a GPCR functions as a receptor for two structurally unrelated ligands, a membrane protein and a sphingolipid. Elucidating Nogo-A/S1PR2 signaling platforms will provide new insights into regulation of synaptic plasticity. ; Recent studies have demonstrated an important role of Nogo-A signaling in the repression of structural and synaptic plasticity in mature neuronal networks of the central nervous system. These insights extended our understanding of Nogo-A's inhibitory function far beyond its well-studied role as axonal-growth inhibitor. Repression is mediated via two different Nogo-A extracellular domains: Nogo-66 and Nogo-A-Δ20. Here, we identify the G-protein coupled receptor S1PR2 as a high-affinity receptor for Nogo-A-Δ20 and demonstrate that S1PR2 binds this domain with sites different from the recently proposed S1P binding pocket. Interfering with S1PR2 activity, either pharmacologically or genetically, prevented Nogo-A-Δ20-mediated inhibitory effects. Similar results were obtained when we blocked G, LARG, and RhoA, components of the downstream signaling pathway. These findings revealed a strong increase in hippocampal and cortical synaptic plasticity when acutely interfering with Nogo-A/S1PR2 signaling, similar to previous results obtained by blocking Nogo-A. We thus provide a novel biological concept of multi-ligand GPCR signaling in which this sphingolipid-activated GPCR is also bound and activated by the high molecular weight membrane protein Nogo-A.
    Keywords: Research Article ; Biology
    ISSN: 1544-9173
    E-ISSN: 1545-7885
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  • 10
    Description: Nogo-A is a membrane protein of the central nervous system (CNS) restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) as a Nogo-A-Δ20-specific receptor. Nogo-A-Δ20 binds S1PR2 on sites distinct from the pocket of the sphingolipid sphingosine 1-phosphate (S1P) and signals via the G protein G13, the Rho GEF LARG, and RhoA. Deleting or blocking S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth and cell spreading. Blockade of S1PR2 strongly enhances long-term potentiation (LTP) in the hippocampus of wild-type but not Nogo-A(-/-) mice, indicating a repressor function of the Nogo-A/S1PR2 axis in synaptic plasticity. A similar increase in LTP was also observed in the motor cortex after S1PR2 blockade. We propose a novel signaling model in which a GPCR functions as a receptor for two structurally unrelated ligands, a membrane protein and a sphingolipid. Elucidating Nogo-A/S1PR2 signaling platforms will provide new insights into regulation of synaptic plasticity.
    Keywords: Brain Research Institute ; 570 Life sciences; biology ; 610 Medicine & health
    Source: University of Zurich
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