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  • Journal article
    Ribet D, Boscaini S, Cauvin C, Siguier M, Mostowy S, Echard A, Cossart Pet al., 2017,

    SUMOylation of human septins is critical for septin filament bundling and cytokinesis.

    , Journal of Cell Biology, Vol: 216, Pages: 4041-4052, ISSN: 0021-9525

    Septins are cytoskeletal proteins that assemble into nonpolar filaments. They are critical in diverse cellular functions, acting as scaffolds for protein recruitment and as diffusion barriers for subcellular compartmentalization. Human septins are encoded by 13 different genes and are classified into four groups based on sequence homology (SEPT2, SEPT3, SEPT6, and SEPT7 groups). In yeast, septins were among the first proteins reported to be modified by SUMOylation, a ubiquitin-like posttranslational modification. However, whether human septins could be modified by small ubiquitin-like modifiers (SUMOs) and what roles this modification may have in septin function remains unknown. In this study, we first show that septins from all four human septin groups can be covalently modified by SUMOs. We show in particular that endogenous SEPT7 is constitutively SUMOylated during the cell cycle. We then map SUMOylation sites to the C-terminal domain of septins belonging to the SEPT6 and SEPT7 groups and to the N-terminal domain of septins from the SEPT3 group. We finally demonstrate that expression of non-SUMOylatable septin variants from the SEPT6 and SEPT7 groups leads to aberrant septin bundle formation and defects in cytokinesis after furrow ingression. Altogether, our results demonstrate a pivotal role for SUMOylation in septin filament bundling and cell division.

  • Journal article
    Berger C, Crepin V, Roumeliotis TI, Wright JC, Carson D, Pevsner-Fischer M, Furniss RCD, Dougan G, Bachash M, Yu L, Clements A, Collins JW, Elinav E, larrouy-maumus G, Choudhary JS, Frankel GMet al., 2017,

    Citrobacter rodentium subverts ATP flux 1 and cholesterol homeostasis in 2 intestinal epithelial cell in vivo

    , Cell Metabolism, Vol: 26, Pages: 738-752.e6, ISSN: 1550-4131

    The intestinal epithelial cells (IECs) that line the gut form a robust line of defense against ingested pathogens. We investigated the impact of infection with the enteric pathogen Citrobacter rodentium on mouse IEC metabolism using global proteomic and targeted metabolomics and lipidomics. The major signatures of the infection were upregulation of the sugar transporter Sglt4, aerobic glycolysis, and production of phosphocreatine, which mobilizes cytosolic energy. In contrast, biogenesis of mitochondrial cardiolipins, essential for ATP production, was inhibited, which coincided with increased levels of mucosal O2 and a reduction in colon-associated anaerobic commensals. In addition, IECs responded to infection by activating Srebp2 and the cholesterol biosynthetic pathway. Unexpectedly, infected IECs also upregulated the cholesterol efflux proteins AbcA1, AbcG8, and ApoA1, resulting in higher levels of fecal cholesterol and a bloom of Proteobacteria. These results suggest that C. rodentium manipulates host metabolism to evade innate immune responses and establish a favorable gut ecosystem.

  • Journal article
    Wen KY, Cameron L, Chappell J, Jensen K, Bell DJ, Kelwick R, Kopniczky M, Davies JC, Filloux A, Freemont PSet al., 2017,

    A Cell-Free Biosensor for Detecting Quorum Sensing Molecules in P. aeruginosa-Infected Respiratory Samples.

    , ACS Synthetic Biology, Vol: 6, Pages: 2293-2301, ISSN: 2161-5063

    Synthetic biology designed cell-free biosensors are a promising new tool for the detection of clinically relevant biomarkers in infectious diseases. Here, we report that a modular DNA-encoded biosensor in cell-free protein expression systems can be used to measure a bacterial biomarker of Pseudomonas aeruginosa infection from human sputum samples. By optimizing the cell-free system and sample extraction, we demonstrate that the quorum sensing molecule 3-oxo-C12-HSL in sputum samples from cystic fibrosis lungs can be quantitatively measured at nanomolar levels using our cell-free biosensor system, and is comparable to LC-MS measurements of the same samples. This study further illustrates the potential of modular cell-free biosensors as rapid, low-cost detection assays that can inform clinical practice.

  • Journal article
    Pallett MA, Crepin VF, Serafini N, Habibzay M, Kotik O, Sanchez-Garrido J, Di Santo J, Shenoy AR, Berger CN, Frankel GMet al., 2017,

    Bacterial Virulence Factor Inhibits Caspase-4/11 Activation in IntestinalEpithelial Cells

    , Mucosal Immunology, Vol: 10, Pages: 602-612, ISSN: 1935-3456

    The human pathogen enteropathogenic Escherichia coli (EPEC), as well as the mouse pathogen Citrobacter rodentium, colonize the gut mucosa via attaching and effacing lesion formation and cause diarrheal diseases. EPEC and C. rodentium type III secretion system (T3SS) effectors repress innate immune responses and infiltration of immune cells. Inflammatory caspases such as caspase'1 and caspase'4/11 are crucial mediators of host defense and inflammation in the gut via their ability to process cytokines such as IL'1β and IL'18. Here we report that the effector NleF binds the catalytic domain of caspase'4 and inhibits its proteolytic activity. Following infection of intestinal epithelial cells (IECs) EPEC inhibited caspase'4 and IL'18 processing in an NleF'dependent manner. Depletion of caspase'4 in IECs prevented the secretion of mature IL'18 in response to infection with EPEC@nleF. NleF'dependent inhibition of caspase'11 in colons of mice prevented IL'18 secretion and neutrophil influx at early stages of C. rodentium infection. Neither wild'type C. rodentium nor C. rodentium@nleF triggered neutrophil infiltration or IL'18 secretion in Cas11 or Casp1/11 deficient mice. Thus, IECs play a key role in modulating early innate immune responses in the gut via a caspase'4/11 ' IL'18 axis, which is targeted by virulence factors encoded by enteric pathogens

  • Journal article
    McCarthy RR, Valentini M, Filloux A, 2017,

    Contribution of Cyclic di-GMP in the Control of Type III and Type VI Secretion in Pseudomonas aeruginosa.

    , Methods Mol Biol, Vol: 1657, Pages: 213-224

    Bacteria produce toxins to enhance their competitiveness in the colonization of an environment as well as during an infection. The delivery of toxins into target cells is mediated by several types of secretion systems, among them our focus is Type III and Type VI Secretion Systems (T3SS and T6SS, respectively). A thorough methodology is provided detailing how to identify if cyclic di-GMP signaling plays a role in the P. aeruginosa toxin delivery mediated by T3SS or T6SS. This includes in vitro preparation of the samples for Western blot analysis aiming at detecting possible c-di-GMP-dependent T3SS/T6SS switch, as well as in vivo analysis using the model organism Galleria mellonella to demonstrate the ecological and pathogenic consequence of the switch between these two secretion systems.

  • Journal article
    Karampatzakis A, Song CZ, Allsopp LP, Filloux A, Rice SA, Cohen Y, Wohland T, Török Pet al., 2017,

    Probing the internal micromechanical properties of Pseudomonas aeruginosa biofilms by Brillouin imaging.

    , NPJ Biofilms Microbiomes, Vol: 3, ISSN: 2055-5008

    Biofilms are organised aggregates of bacteria that adhere to each other or surfaces. The matrix of extracellular polymeric substances that holds the cells together provides the mechanical stability of the biofilm. In this study, we have applied Brillouin microscopy, a technique that is capable of measuring mechanical properties of specimens on a micrometre scale based on the shift in frequency of light incident upon a sample due to thermal fluctuations, to investigate the micromechanical properties of an active, live Pseudomonas aeruginosa biofilm. Using this non-contact and label-free technique, we have extracted information about the internal stiffness of biofilms under continuous flow. No correlation with colony size was found when comparing the averages of Brillouin shifts of two-dimensional cross-sections of randomly selected colonies. However, when focusing on single colonies, we observed two distinct spatial patterns: in smaller colonies, stiffness increased towards their interior, indicating a more compact structure of the centre of the colony, whereas, larger (over 45 μm) colonies were found to have less stiff interiors.

  • Journal article
    Heeb S, Camara M, Filloux A, Williams Pet al., 2017,

    Professor Dieter Haas (1945-2017) OBITUARY

    , FEMS MICROBIOLOGY REVIEWS, Vol: 41, Pages: 597-598, ISSN: 0168-6445
  • Journal article
    Jakobsen TH, Warming AN, Vejborg RM, Moscoso JA, Stegger M, Lorenzen F, Rybtke M, Andersen JB, Petersen R, Andersen PS, Nielsen TE, Tolker-Nielsen T, Filloux A, Ingmer H, Givskov Met al., 2017,

    A broad range quorum sensing inhibitor working through sRNA inhibition

    , Scientific Reports, Vol: 7, ISSN: 2045-2322

    For the last decade, chemical control of bacterial virulence has received considerable attention. Ajoene, a sulfur-rich molecule from garlic has been shown to reduce expression of key quorum sensing regulated virulence factors in the opportunistic pathogen Pseudomonas aeruginosa. Here we show that the repressing effect of ajoene on quorum sensing occurs by inhibition of small regulatory RNAs (sRNA) in P. aeruginosa as well as in Staphylococcus aureus, another important human pathogen that employs quorum sensing to control virulence gene expression. Using various reporter constructs, we found that ajoene lowered expression of the sRNAs RsmY and RsmZ in P. aeruginosa and the small dual-function regulatory RNA, RNAIII in S. aureus, that controls expression of key virulence factors. We confirmed the modulation of RNAIII by RNA sequencing and found that the expression of many QS regulated genes encoding virulence factors such as hemolysins and proteases were lowered in the presence of ajoene in S. aureus. Importantly, our findings show that sRNAs across bacterial species potentially may qualify as targets of anti-virulence therapy and that ajoene could be a lead structure in search of broad-spectrum compounds transcending the Gram negative-positive borderline.

  • Journal article
    Sarkar P, Switzer A, Peters C, Pogliano J, Wigneshweraraj Set al., 2017,

    Phenotypic consequences of RNA polymerase dysregulation in Escherichiacoli

    , Nucleic Acids Research, Vol: 45, Pages: 11131-11143, ISSN: 1362-4962

    Many bacterial adaptive responses to changes in growth conditions due to biotic and abiotic factors involve reprogramming of gene expression at the transcription level. The bacterial RNA polymerase (RNAP), which catalyzes transcription, can thus be considered as the major mediator of cellular adaptive strategies. But how do bacteria respond if a stress factor directly compromises the activity of the RNAP? We used a phage-derived small protein to specifically perturb bacterial RNAP activity in exponentially growing Escherichia coli. Using cytological profiling, tracking RNAP behavior at single-molecule level and transcriptome analysis, we reveal that adaptation to conditions that directly perturb bacterial RNAP performance can result in a biphasic growth behavior and thereby confer the ‘adapted’ bacterial cells an enhanced ability to tolerate diverse antibacterial stresses. The results imply that while synthetic transcriptional rewiring may confer bacteria with the intended desirable properties, such approaches may also collaterally allow them to acquire undesirable traits.

  • Journal article
    Lobato-Marquez D, Mostowy S, 2017,

    Salmonella ubiquitination: ARIH1 enters the fray

    , EMBO Reports, Vol: 18, Pages: 1476-1477, ISSN: 1469-221X

    Ubiquitination is a post-translational modification in which ubiquitin, a 76 amino acid polypeptide, is covalently bound to one or more lysines of a target protein. Ubiquitination is mediated by the coordinated activity of ubiquitin activating (E1), conjugating (E2), and ligating (E3) enzymes. Ubiquitin is widely investigated for its ability to regulate key biological processes in the cell, including protein degradation and host-bacteria interactions. The determinants underlying bacterial ubiquitination, and their precise roles in host defense, have not been fully resolved. In this issue of EMBO reports, Polajnar et al discover that Ring-between-Ring (RBR) E3 ligase ARIH1 (also known as HHARI) is involved in formation of the ubiquitin coat surrounding cytosolic Salmonella [1]. Evidence suggests that ARIH1, in cooperation with E3 ligases LRSAM1 and HOIP, modulates the recognition of intracellular bacteria for cellautonomous immunity.

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