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  • 1. Gavriljuk, Konstantin
    et al.
    Schartner, Jonas
    Seidel, Hans
    Dickhut, Clarissa
    Zahedi, Rene P.
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Kötting, Carsten
    Gerwert, Klaus
    Unraveling the Phosphocholination Mechanism of the Legionella pneumophila Enzyme AnkX2016In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 55, no 31, p. 4375-4385Article in journal (Refereed)
    Abstract [en]

    The intracellular pathogen Legionella pneumophila infects lung macrophages and injects numerous effector proteins into the host cell to establish a vacuole for proliferation. The necessary interference with vesicular trafficking of the host is achieved by modulation of the function of Rab GTPases. The effector protein AnkX chemically modifies Rab1b and Rab35 by covalent phosphocholination of serine or threonine residues using CDP-choline as a donor. So far, the phosphoryl transfer mechanism and the relevance of observed autophosphocholination of AnkX remained disputable. We designed tailored caged compounds to make this type of enzymatic reaction accessible for time-resolved Fourier transform infrared difference spectroscopy. By combining spectroscopic and biochemical methods, we determined that full length AnkX is autophosphocholinated at Ser521, Thr620, and Thr943. However, autophosphocholination loses specificity for these sites in shortened constructs and does not appear to be relevant for the catalysis of the phosphoryl transfer. In contrast, transient phosphocholination of His229 in the conserved catalytic motif might exist as a short-lived reaction intermediate. Upon substrate binding, His229 is deprotonated and locked in this state, being rendered capable of a nucleophilic attack on the pyrophosphate moiety of the substrate. The proton that originated from His229 is transferred to a nearby carboxylic acid residue. Thus, our combined findings support a ping-pong mechanism involving phosphocholination of His229 and subsequent transfer of phosphocholine to the Rab GTPase. Our approach can be extended to the investigation of further nucleotidyl transfer reactions, which are currently of reemerging interest in regulatory pathways of host–pathogen interactions.

  • 2.
    Hedberg, Christian
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Dortmund, Germany.
    Itzen, Aymelt
    Center for Integrated Protein Science Munich, Chemistry Department, Technische Universität München, Garching, Germany.
    Molecular perspectives on protein adenylylation2015In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 10, no 1, p. 12-21Article, review/survey (Refereed)
    Abstract [en]

    In the cell, proteins are frequently modified covalently at specific amino acids with post-translational modifications, leading to a diversification of protein functions and activities. Since the introduction of high-resolution mass spectrometry, new post-translational modifications are constantly being discovered. One particular modification is the adenylylation of mammalian proteins. In adenylylation, adenosine triphosphate (ATP) is utilized to attach an adenosine monophosphate at protein threonine or tyrosine residues via a phosphodiester linkage. Adenylylation is particularly interesting in the context of infections by bacterial pathogens during which mammalian proteins are manipulated through AMP attachment via secreted bacterial factors. In this review, we summarize the role and regulation of enzymatic adenylylation and the mechanisms of catalysis. We also refer to recent methods for the detection of adenylylated proteins by modification-specific antibodies, ATP analogues equipped with chemical handles, and mass spectrometry approaches. Additionally, we review screening approaches for inhibiting adenylylation and briefly discuss related modifications such as phosphocholination and phosphorylation.

  • 3. Heller, K
    et al.
    Ochtrop, Philipp
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Albers, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Itzen, A
    Enzymatic phosphocholination as a tool for protein labeling2015In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 282, p. 12-12Article in journal (Other academic)
    Abstract [en]

    Posttranslational modification (PTM) of proteins is a versatile cellular process to regulate the activities of proteins. The high regioselectivity and catalysis rate of posttranslationally modifying enzymes utilizing high-energy precursors can potentially be exploited to equip proteins or peptide sequences with a label of choice site selectively and efficiently. We and others have recently described and analyzed a new reversible PTM called phosphocholination in which a phosphocholine group is transferred from a cytidine diphosphate choline (CDP-choline) to a serine residue of the small GTPase Rab1 [1–3]. The enzymes AnkX and Lem3 catalyze the modification and the corresponding demodification reactions, respectively. Interestingly, we could demonstrate that the modifying enzyme AnkX only requires a short amino acid sequence for substrate recognition. Therefore, we envision AnkX as a tool for the site directed labeling of target proteins. Here we report on the progress of developing a novel reversible protein labeling strategy based on the enzymes AnkX and Lem3 and on derivatives of CDP-choline. We demonstrate the optimization of AnkX and Lem3 enzyme activities and the identification of optimal and minimal peptide target sequences. Results indicate that indeed arbitrary proteins of interest can be functionalized with phosphocholine derivatives. In summary, this work yields first insights into the development of a CDP-choline based fully reversible protein labeling strategy.

  • 4.
    Heller, Katharina
    et al.
    Center for Integrated Protein Science Munich, Technische Universität München, Department Chemistry, Lichtenbergstrasse 4, 85748 Garching, Germany.
    Ochtrop, Philipp
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Albers, Michael F.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Zauner, Florian B.
    Center for Integrated Protein Science Munich, Technische Universität München, Department Chemistry, Lichtenbergstrasse 4, 85748 Garching, Germany.
    Itzen, Aymelt
    Center for Integrated Protein Science Munich, Technische Universität München, Department Chemistry, Lichtenbergstrasse 4, 85748 Garching, Germany.
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Dortmund, Germany.
    Covalent Protein Labeling by Enzymatic Phosphocholination2015In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 54, no 35, p. 10327-10330Article in journal (Refereed)
    Abstract [en]

    We present a new protein labeling method based on the covalent enzymatic phosphocholination of a specific octapeptide amino acid sequence in intact proteins. The bacterial enzyme AnkX from Legionella pneumophila has been established to transfer functional phosphocholine moieties from synthetically produced CDP-choline derivatives to N-termini, C-termini, and internal loop regions in proteins of interest. Furthermore, the covalent modification can be hydrolytically removed by the action of the Legionella enzyme Lem3. Only a short peptide sequence (eight amino acids) is required for efficient protein labeling and a small linker group (PEG-phosphocholine) is introduced to attach the conjugated cargo.

  • 5. Martinez, Nancy E.
    et al.
    Zimmermann, Tobias J.
    Goosmann, Christian
    Alexander, Tobias
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ziegler, Slava
    Zychlinsky, Arturo
    Waldmann, Herbert
    Tetrahydroisoquinolines: New Inhibitors of Neutrophil Extracellular Trap (NET) Formation2017In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 18, no 10, p. 888-893Article in journal (Refereed)
    Abstract [en]

    Neutrophils are short-lived leukocytes that migrate to sites of infection as part of the acute immune response, where they phagocytose, degranulate, and form neutrophil extracellular traps (NETs). During NET formation, the nuclear lobules of neutrophils disappear and the chromatin expands and, accessorized with neutrophilic granule proteins, is expelled. NETs can be pathogenic in, for example, sepsis, cancer, and autoimmune and cardiovascular diseases. Therefore, the identification of inhibitors of NET formation is of great interest. Screening of a focused library of natural-product-inspired compounds by using a previously validated phenotypic NET assay identified a group of tetrahydroisoquinolines as new NET formation inhibitors. This compound class opens up new avenues for the study of cellular death through NET formation (NETosis) at different stages, and might inspire new medicinal chemistry programs aimed at NET-dependent diseases.

  • 6.
    Moodie, Lindon W. K.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chammaa, Samy
    Kindahl, Tomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Palladium-Mediated Approach to Coumarin-Functionalized Amino Acids2017In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 11, p. 2797-2800Article in journal (Refereed)
    Abstract [en]

    Incorporation of the fluorogenic l-(7-hydroxycoumarin-4-yl)ethylglycine into proteins is a valuable biological tool. Coumarins are typically accessed via the Pechmann reaction, which requires acidic conditions and lacks substrate flexibility. A Pd-mediated coupling is described between o-methoxyboronic acids and a glutamic acid derived (Z)-vinyl triflate, forming latent coumarins. Global deprotection with BBr3 forms the coumarin scaffold in a single step. This mild and scalable route yielded five analogues, including a probe suitable for use at lower pH.

  • 7.
    Moodie, Lindon W. K.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hubert, Madlen
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Zhou, Xin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Albers, Michael Franz
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Photoactivated Colibactin Probes Induce Cellular DNA Damage2019In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 58, no 5, p. 1417-1421Article in journal (Refereed)
    Abstract [en]

    Colibactin is a small molecule produced by certain bacterial species of the human microbiota that harbour the pks genomic island. Pks(+) bacteria induce a genotoxic phenotype in eukaryotic cells and have been linked with colorectal cancer progression. Colibactin is produced in a benign, prodrug form which, prior to export, is enzymatically matured by the producing bacteria to its active form. Although the complete structure of colibactin has not been determined, key structural features have been described including an electrophilic cyclopropane motif, which is believed to alkylate DNA. To investigate the influence of the putative "warhead" and the prodrug strategy on genotoxicity, a series of photolabile colibactin probes were prepared that upon irradiation induced a pks(+) like phenotype in HeLa cells. Furthermore, results from DNA cross-linking and imaging studies of clickable analogues enforce the hypothesis that colibactin effects its genotoxicity by directly targeting DNA.

  • 8.
    Ochtrop, Philipp
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ernst, Stefan
    Itzen, Aymelt
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Exploring the Substrate Scope of the Bacterial Phosphocholine Transferase AnkX for Versatile Protein Functionalization2019In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 20, no 18, p. 2336-2340Article in journal (Refereed)
    Abstract [en]

    Site-specific protein functionalization has become an indispensable tool in modern life sciences. Here, tag-based enzymatic protein functionalization techniques are among the most versatilely applicable approaches. However, many chemo-enzymatic functionalization strategies suffer from low substrate scopes of the enzymes utilized for functional labeling probes. We report on the wide substrate scope of the bacterial enzyme AnkX towards derivatized CDP-choline analogues and demonstrate that AnkX-catalyzed phosphocholination can be used for site-specific one- and two-step protein labeling with a broad array of different functionalities, displaying fast second-order transfer rates of 5x10(2) to 1.8x10(4) m(-1) s(-1). Furthermore, we also present a strategy for the site-specific dual labeling of proteins of interest, based on the exploitation of AnkX and the delabeling function of the enzyme Lem3. Our results contribute to the wide field of protein functionalization, offering an attractive chemo-enzymatic tag-based modification strategy for in vitro labeling.

  • 9.
    Ochtrop, Philipp
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ernst, Stefan
    Itzen, Aymelt
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Exploring the substrate scope of the phosphocholine transferase AnkX for versatile protein functionalisationManuscript (preprint) (Other academic)
  • 10.
    Ochtrop, Philipp
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Swart, Leonie
    Simon, Sylvia
    Janning, Petra
    Dickhut, Clarissa
    Zahedi, Rene, P.
    Hilbi, Hubert
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Identification of cellular protein targets for the Legionella pneumophila phosphocholinating effector AnkXManuscript (preprint) (Other academic)
  • 11. Pandey, Sunil Kumar
    et al.
    Guttormsen, Yngve
    Haug, Bengt Erik
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bayer, Annette
    A Concise Total Synthesis of Breitfussin A and B2015In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, no 1, p. 122-125Article in journal (Refereed)
    Abstract [en]

    The first total synthesis of breitfussin A and B is described. The approach features two palladium-catalyzed cross-couplings installing the indole and pyrrole onto the oxazole core and selective lithiation/iodination of a common indole-oxazole fragment providing 2,4-diiodinated or 2-iodinated oxazoles as potential precursors for breitfussin A and B, respectively. An unexpected acid promoted deiodination was utilized in the synthesis of breitfussin B. Comparison of the synthetic material with previously reported spectral data of isolated breitfussin A and B verified the structure of the breitfussin framework.

  • 12. Paulsen, Marianne H.
    et al.
    Karlsen, Eskil Andre
    Ausbacher, Dominik
    Anderssen, Trude
    Bayer, Annette
    Ochtrop, Philipp
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Haug, Tor
    Sollid, Johanna U. Ericson
    Strøm, Morten B.
    An amphipathic cyclic tetrapeptide scaffold containing halogenated β2,2-amino acids with activity against multiresistant bacteria2018In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 24, no 10, article id UNSP e3117Article in journal (Refereed)
    Abstract [en]

    The present study describes the synthesis and biological studies of a small series of head-to-tail cyclic tetrapeptides of the general structure c(Lys‐β2,2‐Xaa‐Lys) containing one lipophilic β2,2-amino acid and Lys, Gly, Ala, or Phe as the Xaa residue in the sequence. The peptides were investigated for antimicrobial activity against gram-positive and gram-negative reference strains and 30 multiresistant clinical isolates including strains with extended spectrum β-lactamase-carbapenemase (ESBL-CARBA) production. Toxicity was determined against human red blood cells. The most potent peptides showed high activity against the gram-positive clinical isolates with minimum inhibitory concentrations of 4-8μg/mL and low haemolytic activity. The combination of high antimicrobial activity and low toxicity shows that these cyclic tetrapeptides containing lipophilic β2,2-amino acids form a valuable scaffold for designing novel antimicrobial agents.

  • 13. Qian, Yong
    et al.
    Schuermann, Marc
    Janning, Petra
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Waldmann, Herbert
    Activity-Based Proteome Profiling Probes Based on Woodward's Reagent K with Distinct Target Selectivity2016In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 55, no 27, p. 7766-7771Article in journal (Refereed)
    Abstract [en]

    Woodward's reagent K (WRK) is a reactive heterocyclic compound that has been employed in protein chemistry to covalently and unspecifically label proteins at nucleophilic amino acids, notably at histidine and cysteine. We have developed a panel of WRK-derived activity-based probes and show that surprisingly and unexpectedly, these probes are fairly selective for a few proteins in the human proteome. The WRK-derived probes show unique reactivity towards the catalytic N-terminal proline in the macrophage migration inhibitory factor (MIF) and can be used to label and, if equipped with a fluorophore, to image MIF activities in living cells.

  • 14.
    Rogne, Per
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rosselin, Marie
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    H. Sauer, Uwe
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wolf-Watz, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Molecular mechanism of ATP versus GTP selectivity of adenylate kinase2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 12, p. 3012-3017Article in journal (Refereed)
    Abstract [en]

    Enzymatic substrate selectivity is critical for the precise control of metabolic pathways. In cases where chemically related substrates are present inside cells, robust mechanisms of substrate selectivity are required. Here, we report the mechanism utilized for catalytic ATP versus GTP selectivity during adenylate kinase (Adk) -mediated phosphorylation of AMP. Using NMR spectroscopy we found that while Adk adopts a catalytically competent and closed structural state in complex with ATP, the enzyme is arrested in a catalytically inhibited and open state in complex with GTP. X-ray crystallography experiments revealed that the interaction interfaces supporting ATP and GTP recognition, in part, are mediated by coinciding residues. The mechanism provides an atomic view on how the cellular GTP pool is protected from Adk turnover, which is important because GTP has many specialized cellular functions. In further support of this mechanism, a structure-function analysis enabled by synthesis of ATP analogs suggests that a hydrogen bond between the adenine moiety and the backbone of the enzyme is vital for ATP selectivity. The importance of the hydrogen bond for substrate selectivity is likely general given the conservation of its location and orientation across the family of eukaryotic protein kinases.

  • 15. Schell, Ursula
    et al.
    Simon, Sylvia
    Sahr, Tobias
    Hager, Dominik
    Albers, Michael F
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kessler, Aline
    Fahrnbauer, Felix
    Trauner, Dirk
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Buchrieser, Carmen
    Hilbi, Hubert
    The α-hydroxyketone LAI-1 regulates motility, Lqs-dependent phosphorylation signaling and gene expression of Legionella pneumophila2016In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 99, no 4, p. 778-793Article in journal (Refereed)
    Abstract [en]

    The causative agent of Legionnaires' disease, Legionella pneumophila, employs the autoinducer compound LAI-1 (3-hydroxypentadecane-4-one) for cell–cell communication. LAI-1 is produced and detected by the Lqs (Legionella quorum sensing) system, comprising the autoinducer synthase LqsA, the sensor kinases LqsS and LqsT, as well as the response regulator LqsR. Lqs-regulated processes include pathogen–host interactions, production of extracellular filaments and natural competence for DNA uptake. Here we show that synthetic LAI-1 promotes the motility of L. pneumophila by signalling through LqsS/LqsT and LqsR. Upon addition of LAI-1, autophosphorylation of LqsS/LqsT by [γ-32P]-ATP was inhibited in a dose-dependent manner. In contrast, the Vibrio cholerae autoinducer CAI-1 (3-hydroxytridecane-4-one) promoted the phosphorylation of LqsS (but not LqsT). LAI-1 did neither affect the stability of phospho-LqsS or phospho-LqsT, nor the dephosphorylation by LqsR. Transcriptome analysis of L. pneumophila treated with LAI-1 revealed that the compound positively regulates a number of genes, including the non-coding RNAs rsmY and rsmZ, and negatively regulates the RNA-binding global regulator crsA. Accordingly, LAI-1 controls the switch from the replicative to the transmissive growth phase of L. pneumophila. In summary, the findings indicate that LAI-1 regulates motility and the biphasic life style of L. pneumophila through LqsS- and LqsT-dependent phosphorylation signalling.

  • 16.
    Shukla, Lakshmi
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Moodie, Lindon W. K.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kindahl, Tomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis and Spectroscopic Properties of Fluorinated Coumarin Lysine Derivatives2018In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 83, no 8, p. 4792-4799Article in journal (Refereed)
    Abstract [en]

    The site-selective incorporation of fluorescent amino acids into proteins has emerged as a valuable alternative to expressible protein reporters. For successful application, a robust and scalable, yet flexible, route to non-natural amino acids is required. This work describes an improved synthesis of coumarin-conjugated lysine derivatives where fluorinated variants are accessed. These analogues can be utilized at low pH and should find application probing biological processes that operate under acidic conditions.

  • 17. Simon, Sylvia
    et al.
    Schell, Ursula
    Heuer, Natalie
    Hager, Dominik
    Albers, Michael F
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Matthias, Jan
    Fahrnbauer, Felix
    Trauner, Dirk
    Eichinger, Ludwig
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Dortmund, Germany.
    Hilbi, Hubert
    Inter-kingdom Signaling by the Legionella Quorum Sensing Molecule LAI-1 Modulates Cell Migration through an IQGAP1-Cdc42-ARHGEF9-Dependent Pathway2015In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 12, article id e1005307Article in journal (Refereed)
    Abstract [en]

    Small molecule signaling promotes the communication between bacteria as well as between bacteria and eukaryotes. The opportunistic pathogenic bacterium Legionella pneumophila employs LAI-1 (3-hydroxypentadecane-4-one) for bacterial cell-cell communication. LAI-1 is produced and detected by the Lqs (Legionella quorum sensing) system, which regulates a variety of processes including natural competence for DNA uptake and pathogen-host cell interactions. In this study, we analyze the role of LAI-1 in inter-kingdom signaling. L. pneumophila lacking the autoinducer synthase LqsA no longer impeded the migration of infected cells, and the defect was complemented by plasmid-borne lqsA. Synthetic LAI-1 dose-dependently inhibited cell migration, without affecting bacterial uptake or cytotoxicity. The forward migration index but not the velocity of LAI-1-treated cells was reduced, and the cell cytoskeleton appeared destabilized. LAI-1-dependent inhibition of cell migration involved the scaffold protein IQGAP1, the small GTPase Cdc42 as well as the Cdc42-specific guanine nucleotide exchange factor ARHGEF9, but not other modulators of Cdc42, or RhoA, Rac1 or Ran GTPase. Upon treatment with LAI-1, Cdc42 was inactivated and IQGAP1 redistributed to the cell cortex regardless of whether Cdc42 was present or not. Furthermore, LAI-1 reversed the inhibition of cell migration by L. pneumophila, suggesting that the compound and the bacteria antagonistically target host signaling pathway(s). Collectively, the results indicate that the L. pneumophila quorum sensing compound LAI-1 modulates migration of eukaryotic cells through a signaling pathway involving IQGAP1, Cdc42 and ARHGEF9.

  • 18.
    Wolf-Watz, Magnus
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rogne, Per
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sauer-Eriksson, A. Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sauer, Uwe H.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Positive and Negative Substrate Interference Supported by Coinciding Enzyme Residues2019In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, no 3, p. 485A-485AArticle in journal (Other academic)
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