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Berlin Brandenburg

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  • 1
    Language: English
    In: Science (New York, N.Y.), 16 November 2012, Vol.338(6109), pp.963-7
    Description: Salmonella enterica is an intracellular bacterial pathogen that replicates within membrane-bound vacuoles through the action of effector proteins translocated into host cells. Salmonella vacuoles have characteristics of lysosomes but are reduced in hydrolytic enzymes transported by mannose-6-phosphate receptors (MPRs). We found that the effector SifA subverted Rab9-dependent retrograde trafficking of MPRs, thereby attenuating lysosome function. This required binding of SifA to its host cell target SKIP/PLEKHM2. Furthermore, SKIP regulated retrograde trafficking of MPRs in noninfected cells. Translocated SifA formed a stable complex with SKIP and Rab9 in infected cells. Sequestration of Rab9 by SifA-SKIP accounted for the effect of SifA on MPR transport and lysosome function. Growth of Salmonella increased in cells with reduced lysosomal activity and decreased in cells with higher lysosomal activity. These results suggest that Salmonella vacuoles undergo fusion with lysosomes whose potency has been reduced by SifA.
    Keywords: Bacterial Proteins -- Metabolism ; Glycoproteins -- Metabolism ; Lysosomes -- Metabolism ; Receptor, IGF Type 2 -- Metabolism ; Salmonella Enterica -- Metabolism
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: The Journal of biological chemistry, 28 September 2018, Vol.293(39), pp.15316-15329
    Description: The closely related type III secretion system zinc metalloprotease effector proteins GtgA, GogA, and PipA are translocated into host cells during infection. They then cleave nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) transcription factor subunits, dampening activation of the NF-κB signaling pathway and thereby suppressing host immune responses. We demonstrate here that GtgA, GogA, and PipA cleave a subset of NF-κB subunits, including p65, RelB, and cRel but not NF-κB1 and NF-κB2, whereas the functionally similar type III secretion system effector NleC of enteropathogenic and enterohemorrhagic cleaved all five NF-κB subunits. Mutational analysis of NF-κB subunits revealed that a single nonconserved residue in NF-κB1 and NF-κB2 that corresponds to the P1' residue Arg-41 in p65 prevents cleavage of these subunits by GtgA, GogA, and PipA, explaining the observed substrate specificity of these enzymes. Crystal structures of GtgA in its apo-form and in complex with the p65 N-terminal domain explained the importance of the P1' residue. Furthermore, the pattern of interactions suggested that GtgA recognizes NF-κB subunits by mimicking the shape and negative charge of the DNA phosphate backbone. Moreover, structure-based mutational analysis of GtgA uncovered amino acids that are required for the interaction of GtgA with p65, as well as those that are required for full activity of GtgA in suppressing NF-κB activation. This study therefore provides detailed and critical insight into the mechanism of substrate recognition by this family of proteins important for bacterial virulence.
    Keywords: Gtga ; Nf-Κb ; Salmonella Enterica ; Bacterial Effectors ; Bacterial Pathogenesis ; Metalloprotease ; Substrate Specificity ; Type III Secretion System (T3ss) ; Virulence Factor ; Escherichia Coli -- Chemistry ; Metalloproteases -- Chemistry ; Salmonella Infections -- Genetics ; Salmonella Enterica -- Chemistry
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 3
    In: Nature, 2012, Vol.482(7385), p.414
    Description: Autophagy defends the mammalian cytosol against bacterial infection1,2,3. Efficient pathogen engulfment is mediated by cargo-selecting autophagy adaptors that rely on unidentified pattern-recognition or danger receptors to label invading pathogens as autophagy cargo, typically by polyubiquitin coating4,5,6,7,8,9. Here we show in human cells that galectin 8 (also known as LGALS8), a cytosolic lectin, is a danger receptor that restricts Salmonella proliferation. Galectin 8 monitors endosomal and lysosomal integrity and detects bacterial invasion by binding host glycans exposed on damaged Salmonella-containing vacuoles. By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. Galectin-8-dependent recruitment of NDP52 to Salmonella-containing vesicles is transient and followed by ubiquitin-dependent NDP52 recruitment. Because galectin 8 also detects sterile damage to endosomes or lysosomes, as well as invasion by Listeria or Shigella, we suggest that galectin 8 serves as a versatile receptor for vesicle-damaging pathogens. Our results illustrate how cells deploy the danger receptor galectin 8 to combat infection by monitoring endosomal and lysosomal integrity on the basis of the specific lack of complex carbohydrates in the cytosol.
    Keywords: Science & Technology ; Multidisciplinary Sciences ; Science & Technology - Other Topics ; Genome-Wide Association ; Adapter Proteins ; Mammalian-Cells ; Crohns-Disease ; Immunity ; Ubiquitin ; Susceptibility ; Salmonella ; Inflammation ; Recognition ; Autophagy ; Cell Proliferation ; Cytoplasm ; Cytoplasmic Vesicles ; Endosomes ; Galectins ; Hela Cells ; Humans ; Lysosomes ; Nuclear Proteins ; Salmonella Infections ; Salmonella Typhimurium ; Hela Cells ; Cytoplasm ; Cytoplasmic Vesicles ; Endosomes ; Lysosomes ; Humans ; Salmonella Typhimurium ; Salmonella Infections ; Galectins ; Nuclear Proteins ; Cell Proliferation ; Autophagy ; MD Multidisciplinary ; General Science & Technology;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
    Language: English
    In: Science (New York, N.Y.), 07 December 2018, Vol.362(6419), pp.1156-1160
    Description: Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.
    Keywords: Drug Resistance, Bacterial ; Host-Pathogen Interactions -- Immunology ; Macrophages -- Immunology ; Salmonella Infections -- Drug Therapy ; Salmonella Typhimurium -- Metabolism ; Type III Secretion Systems -- Metabolism
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 5
    Language: English
    In: The Journal of biological chemistry, 06 April 2018, Vol.293(14), pp.5064-5078
    Description: The -secreted effector SseK3 translocates into host cells, targeting innate immune responses, including NF-κB activation. SseK3 is a glycosyltransferase that transfers an -acetylglucosamine (GlcNAc) moiety onto the guanidino group of a target arginine, modulating host cell function. However, a lack of structural information has precluded elucidation of the molecular mechanisms in arginine and GlcNAc selection. We report here the crystal structure of SseK3 in its apo form and in complex with hydrolyzed UDP-GlcNAc. SseK3 possesses the typical glycosyltransferase type-A (GT-A)-family fold and the metal-coordinating DD motif essential for ligand binding and enzymatic activity. Several conserved residues were essential for arginine GlcNAcylation and SseK3-mediated inhibition of NF-κB activation. Isothermal titration calorimetry revealed SseK3's preference for manganese coordination. The pattern of interactions in the substrate-bound SseK3 structure explained the selection of the primary ligand. Structural rearrangement of the C-terminal residues upon ligand binding was crucial for SseK3's catalytic activity, and NMR analysis indicated that SseK3 has limited UDP-GlcNAc hydrolysis activity. The release of free -acetyl α-d-glucosamine, and the presence of the same molecule in the SseK3 active site, classified it as a retaining glycosyltransferase. A glutamate residue in the active site suggested a double-inversion mechanism for the arginine -glycosylation reaction. Homology models of SseK1, SseK2, and the orthologue NleB1 reveal differences in the surface electrostatic charge distribution, possibly accounting for their diverse activities. This first structure of a retaining GT-A arginine -glycosyltransferase provides an important step toward a better understanding of this enzyme class and their roles as bacterial effectors.
    Keywords: Gt-A Family ; Salmonella Enterica ; Ssek3 ; Udp-Glcnac ; X-Ray Crystallography ; Arginine Modification ; Bacterial Effectors ; Bacterial Toxin ; Enzyme Mechanism ; Glycosyltransferase ; Glycosyltransferase Type-A ; Protein Structure ; Structural Analysis
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 6
    Language: English
    In: Infection and immunity, June 2017, Vol.85(6)
    Keywords: Medicine ; Biology;
    ISSN: 00199567
    E-ISSN: 1098-5522
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  • 7
    Language: English
    In: Infection and immunity, September 2018, Vol.86(9)
    Description: In order to deploy virulence factors at appropriate times and locations, microbes must rapidly sense and respond to various metabolite signals. Previously, we showed a transient elevation of the methionine-derived metabolite methylthioadenosine (MTA) concentration in serum during systemic serovar Typhimurium infection. Here we explored the functional consequences of increased MTA concentrations on Typhimurium virulence. We found that MTA, but not other related metabolites involved in polyamine synthesis and methionine salvage, reduced motility, host cell pyroptosis, and cellular invasion. Further, we developed a genetic model of increased bacterial endogenous MTA production by knocking out the master repressor of the methionine regulon, Like MTA-treated Typhimurium, the Δ mutant displayed reduced motility, host cell pyroptosis, and invasion. These phenotypic effects of MTA correlated with suppression of flagellar and pathogenicity island 1 (SPI-1) networks. Typhimurium Δ had reduced virulence in oral and intraperitoneal infection of C57BL/6J mice independently of the effects of MTA on SPI-1. Finally, Δ bacteria induced a less severe inflammatory cytokine response in a mouse sepsis model. Together, these data indicate that exposure of Typhimurium to MTA or disruption of the bacterial methionine metabolism pathway suppresses Typhimurium virulence.
    Keywords: SPI-1 ; Salmonella ; Flagellar Motility ; Inflammation ; Metj ; Metabolism ; Methionine Salvage ; Methylthioadenosine ; Virulence Regulation ; Adenosine -- Metabolism ; Methionine -- Metabolism ; Salmonella Typhimurium -- Pathogenicity
    ISSN: 00199567
    E-ISSN: 1098-5522
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  • 8
    Language: English
    In: Infection and immunity, March 2017, Vol.85(3)
    Description: Within host cells such as macrophages, translocates virulence (effector) proteins across its vacuolar membrane via the SPI-2 type III secretion system. Previously, it was shown that when expressed ectopically, the effectors SseK1 and SseK3 inhibit tumor necrosis factor alpha (TNF-α)-induced NF-κB activation. In this study, we show that ectopically expressed SseK1, SseK2, and SseK3 suppress TNF-α-induced, but not Toll-like receptor 4- or interleukin-induced, NF-κB activation. Inhibition required a DXD motif in SseK1 and SseK3, which is essential for the transfer of -acetylglucosamine to arginine residues (arginine-GlcNAcylation). During macrophage infection, SseK1 and SseK3 inhibited NF-κB activity in an additive manner. SseK3-mediated inhibition of NF-κB activation did not require the only known host-binding partner of this effector, the E3-ubiquitin ligase TRIM32. SseK proteins also inhibited TNF-α-induced cell death during macrophage infection. Despite SseK1 and SseK3 inhibiting TNF-α-induced apoptosis upon ectopic expression in HeLa cells, the percentage of infected macrophages undergoing apoptosis was SseK independent. Instead, SseK proteins inhibited necroptotic cell death during macrophage infection. SseK1 and SseK3 caused GlcNAcylation of different proteins in infected macrophages, suggesting that these effectors have distinct substrate specificities. Indeed, SseK1 caused the GlcNAcylation of the death domain-containing proteins FADD and TRADD, whereas SseK3 expression resulted in weak GlcNAcylation of TRADD but not FADD. Additional, as-yet-unidentified substrates are likely to explain the additive phenotype of a strain lacking both SseK1 and SseK3.
    Keywords: Nf-Κb Signaling ; Salmonella ; Cell Death ; Necroptosis ; Signal Transduction ; Type III Secretion Systems ; Bacterial Proteins -- Metabolism ; Macrophages -- Metabolism ; Nf-Kappa B -- Metabolism ; Salmonella -- Physiology
    ISSN: 00199567
    E-ISSN: 1098-5522
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  • 9
    Language: English
    In: The Journal of cell biology, 23 June 2014, Vol.205(6), pp.847-62
    Description: The regulated turnover of endoplasmic reticulum (ER)-resident membrane proteins requires their extraction from the membrane lipid bilayer and subsequent proteasome-mediated degradation. Cleavage within the transmembrane domain provides an attractive mechanism to facilitate protein dislocation but has never been shown for endogenous substrates. To determine whether intramembrane proteolysis, specifically cleavage by the intramembrane-cleaving aspartyl protease signal peptide peptidase (SPP), is involved in this pathway, we generated an SPP-specific somatic cell knockout. In a stable isotope labeling by amino acids in cell culture-based proteomics screen, we identified HO-1 (heme oxygenase-1), the rate-limiting enzyme in the degradation of heme to biliverdin, as a novel SPP substrate. Intramembrane cleavage by catalytically active SPP provided the primary proteolytic step required for the extraction and subsequent proteasome-dependent degradation of HO-1, an ER-resident tail-anchored protein. SPP-mediated proteolysis was not limited to HO-1 but was required for the dislocation and degradation of additional tail-anchored ER-resident proteins. Our study identifies tail-anchored proteins as novel SPP substrates and a specific requirement for SPP-mediated intramembrane cleavage in protein turnover.
    Keywords: Aspartic Acid Endopeptidases -- Physiology ; Membrane Proteins -- Metabolism
    ISSN: 00219525
    E-ISSN: 1540-8140
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  • 10
    Language: English
    In: Cell Host & Microbe, 09 August 2017, Vol.22(2), pp.217-231
    Description: Serovars of cause both gastrointestinal and systemic diseases in a broad range of mammalian hosts, including humans. virulence depends in part on its pathogenicity island 2 type III secretion system (SPI-2 T3SS), which is required to translocate at least 28 effector proteins from vacuolar-resident bacteria into host cells. Comparative genomic analysis reveals that all serovars encode a subset of “core” effectors, suggesting that they are critical for virulence in different hosts. An additional subset of effectors is found sporadically throughout different serovars, and several inhibit activation of the innate immune system. In this Review, we summarize the biochemical activities, host cell interaction partners, and physiological functions of SPI-2 T3SS effectors in the context of the selective pressures encountered by . We also consider some of the remaining challenges to achieve a unified understanding of how effector activities work together to promote virulence. The SPI-2 type III secretion system transfers a large number of effector proteins to host cells. In this Review, Holden and colleagues summarize the biochemical activities, host cell interaction partners, and physiological functions of these effectors in the context of the selective pressures encountered by in vivo.
    Keywords: Salmonella ; Effector ; Type III Secretion System ; SPI-2 ; Pathogenicity Island ; Virulence ; Bacterial Pathogen ; Biology
    ISSN: 1931-3128
    E-ISSN: 1934-6069
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