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Staphylococcus aureus Survives with a Minimal Peptidoglycan Synthesis Machine but Sacrifices Virulence and Antibiotic Resistance
Get PDFMany important cellular processes are performed by molecular machines, composed of multiple proteins that physically interact to execute biological functions. An example is the bacterial peptidoglycan (PG) synthesis machine, responsible for the synthesis of the main component of the cell wall and the target of many contemporary antibiotics. One approach for the identification of essential components of a cellular machine involves the determination of its minimal protein composition. Staphylococcus aureus is a Gram-positive pathogen, renowned for its resistance to many commonly used antibiotics and prevalence in hospitals. Its genome encodes a low number of proteins with PG synthesis activity (9 proteins), when compared to other model organisms, and is therefore a good model for the study of a minimal PG synthesis machine. We deleted seven of the nine genes encoding PG synthesis enzymes from the S. aureus genome without affecting normal growth or cell morphology, generating a strain capable of PG biosynthesis catalyzed only by two penicillin-binding proteins, PBP1 and the bi-functional PBP2. However, multiple PBPs are important in clinically relevant environments, as bacteria with a minimal PG synthesis machinery became highly susceptible to cell wall-targeting antibiotics, host lytic enzymes and displayed impaired virulence in a Drosophila infection model which is dependent on the presence of specific peptidoglycan receptor proteins, namely PGRP-SA. The fact that S. aureus can grow and divide with only two active PG synthesizing enzymes shows that most of these enzymes are redundant in vitro and identifies the minimal PG synthesis machinery of S. aureus. However a complex molecular machine is important in environments other than in vitro growth as the expendable PG synthesis enzymes play an important role in the pathogenicity and antibiotic resistance of S. aureus.FCT grant: (PEst-OE/EQB/LA0004/2011), National Institute of General Medical Sciences grant: (GM85024), FCT fellowships: (SFRH/BPD/23812/2005, SFRH/BD/41119/2007, SFRH/BD/28440/2006), European Molecular Biology Organization long-term fellowship: (ALTF 782–2012)
Asymptomatic Plasmodium falciparum infection in children is associated with increased auto-antibody production, high IL-10 plasma levels and antibodies to merozoite surface protein 3
Get PDFMechanisms of acquired protection to malaria in asymptomatic Plasmodium falciparum carriers are only partially understood. Among them, the role plays by the self-reactive antibodies has not been clarified yet. In this study, the relationship between repertoires of circulating self-reactive and parasite-specific immunoglobulin G (IgG), their correlation with cytokine levels, and their association with protection against malaria was investigated in asymptomatic Plasmodium falciparum-infected Gabonese children.Centre National de la Recherche Scientifique-Laboratoires Européen Associés ‘Génétique et développement de la tolérance naturelle’ programme, French Ministry of Research and LabEx Parafrap - PAL+ programme: (ANR-11-LABX-0024), FCT fellowships: postdoctoral fellowship and visiting scientist fellowship, Agence Universitaire de la Francophonie (AUF) fellowship, Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) fellowship
Evolutionary Patterns in Coiled-Coils
Get PDFModels of protein evolution are used to describe evolutionary processes, for phylogenetic analyses and homology detection. Widely used general models of protein evolution are biased toward globular domains and lack resolution to describe evolutionary processes for other protein types. As three-dimensional structure is a major constraint to protein evolution, specific models have been proposed for other types of proteins. Here, we consider evolutionary patterns in coiled-coil forming proteins. Coiled-coils are widespread structural domains, formed by a repeated motif of seven amino acids (heptad repeat). Coiled-coil forming proteins are frequently rods and spacers, structuring both the intracellular and the extracellular spaces that often form protein interaction interfaces. We tested the hypothesis that due to their specific structure the associated evolutionary constraints differ from those of globular proteins. We showed that substitution patterns in coiled-coil regions are different than those observed in globular regions, beyond the simple heptad repeat. Based on these substitution patterns we developed a coiled-coil specific (CC) model that in the context of phylogenetic reconstruction outperforms general models in tree likelihood, often leading to different topologies. For multidomain proteins containing both a coiled-coil region and a globular domain, we showed that a combination of the CC model and a general one gives higher likelihoods than a single model. Finally, we showed that the model can be used for homology detection to increase search sensitivity for coiled-coil proteins. The CC model, software, and other supplementary materials are available at http://www.evocell.org/cgl/resources (last accessed January 29, 2015).FCT fellowship: (SFRH/BD/51880/2012)
The retinal determination gene dachshund restricts cell proliferation by limiting the activity of the Homothorax-Yorkie complex
Get PDFThe Drosophila transcriptional co-activator protein Yorkie and its vertebrate orthologs YAP and TAZ are potent oncogenes, whose activity is normally kept in check by the upstream Hippo kinase module. Upon its translocation into the nucleus, Yorkie forms complexes with several tissue-specific DNA-binding partners, which help to define the tissue-specific target genes of Yorkie. In the progenitor cells of the eye imaginal disc, the DNA-binding transcription factor Homothorax is required for Yorkie-promoted proliferation and survival through regulation of the bantam microRNA (miRNA). The transit from proliferating progenitors to cell cycle quiescent precursors is associated with the progressive loss of Homothorax and gain of Dachshund, a nuclear protein related to the Sno/Ski family of co-repressors. We have identified Dachshund as an inhibitor of Homothorax-Yorkie-mediated cell proliferation. Loss of dachshund induces Yorkie-dependent tissue overgrowth. Conversely, overexpressing dachshund inhibits tissue growth, prevents Yorkie or Homothorax-mediated cell proliferation of disc epithelia and restricts the transcriptional activity of the Yorkie-Homothorax complex on the bantam enhancer in Drosophila cells. In addition, Dachshund collaborates with the Decapentaplegic receptor Thickveins to repress Homothorax and Cyclin B expression in quiescent precursors. The antagonistic roles of Homothorax and Dachshund in Yorkie activity, together with their mutual repression, ensure that progenitor and precursor cells are under distinct proliferation regimes. Based on the crucial role of the human dachshund homolog DACH1 in tumorigenesis, our work suggests that DACH1 might prevent cellular transformation by limiting the oncogenic activity of YAP and/or TAZ.Spanish Ministry of Economy and Competitiveness (MINECO), EU Feder Funds: (BFU2012-34324), Consolider 'From Genes to Shape' (MICINN), FCT fellowships: (SFRH/BPD/46983/2008, IF/01031/2012)
Rootletin organizes the ciliary rootlet to achieve neuron sensory function in Drosophila
Get PDFCilia are essential for cell signaling and sensory perception. In many cell types, a cytoskeletal structure called the ciliary rootlet links the cilium to the cell body. Previous studies indicated that rootlets support the long-term stability of some cilia. Here we report that Drosophila melanogaster Rootletin (Root), the sole orthologue of the mammalian paralogs Rootletin and C-Nap1, assembles into rootlets of diverse lengths among sensory neuron subtypes. Root mutant neurons lack rootlets and have dramatically impaired sensory function, resulting in behavior defects associated with mechanosensation and chemosensation. Root is required for cohesion of basal bodies, but the cilium structure appears normal in Root mutant neurons. We show, however, that normal rootlet assembly requires centrioles. The N terminus of Root contains a conserved domain and is essential for Root function in vivo. Ectopically expressed Root resides at the base of mother centrioles in spermatocytes and localizes asymmetrically to mother centrosomes in neuroblasts, both requiring Bld10, a basal body protein with varied functions.National Institutes of Health grant: (GM068758)
Second-order structure function analysis of scatterometer winds over the Tropical Pacific
Get PDFKolmogorov second-order structure functions are used to quantify and compare the small-scale information contained in near-surface ocean wind products derived from measurements by ASCAT on MetOp-A and SeaWinds on QuikSCAT. Two ASCAT and three SeaWinds products are compared in nine regions (classified as rainy or dry) in the tropical Pacific between 10°S and 10°N and 140° and 260°E for the period November 2008 to October 2009. Monthly and regionally averaged longitudinal and transverse structure functions are calculated using along-track samples. To ease the analysis, the following quantities were estimated for the scale range 50 to 300 km and used to intercompare the wind products: (i) structure function slopes, (ii) turbulent kinetic energies ( inline image), and (iii) vorticity-to-divergence ratios. All wind products are in good qualitative agreement, but also have important differences. Structure function slopes and inline image differ per wind product, but also show a common variation over time and space. Independent of wind product, longitudinal slopes decrease when sea surface temperature exceeds the threshold for onset of deep convection (about 28°C). In rainy areas and in dry regions during rainy periods, ASCAT has larger divergent inline image than SeaWinds, while SeaWinds has larger vortical inline image than ASCAT. Differences between SeaWinds and ASCAT vortical inline image and vorticity-to-divergence ratios for the convectively active months of each region are large.EUMETSAT as part of the SAF Visiting Scientists programme
Evidence of IL-17, IP-10, and IL-10 involvement in multiple-organ dysfunction and IL-17 pathway in acute renal failure associated to Plasmodium falciparum malaria
Get PDFPlasmodium falciparum malaria in India is characterized by high rates of severe disease, with multiple organ dysfunction (MOD)-mainly associated with acute renal failure (ARF)-and increased mortality. The objective of this study is to identify cytokine signatures differentiating severe malaria patients with MOD, cerebral malaria (CM), and cerebral malaria with MOD (CM-MOD) in India. We have previously shown that two cytokines clusters differentiated CM from mild malaria in Maharashtra. Hence, we also aimed to determine if these cytokines could discriminate malaria subphenotypes in Odisha.Indo-French Centre for the Promotion of Advanced Research (IFCPAR project No 3703), International Associated Laboratory Systems Immunology and Genetics of Infectious Diseases (LIA SIGID, CNRS, Lille University and the Department of Biotechnology (DBT), Ministry of Science and Technology of India and the ANR LAbEx Parafrap)
The ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation
Get PDFActivation of NF-κB-dependent transcription represents an important hallmark of inflammation. While the acute inflammatory response is per se beneficial, it can become deleterious if its spatial and temporal profile is not tightly controlled. Classically, NF-κB activity is limited by cytoplasmic retention of the NF-κB dimer through binding to inhibitory IκB proteins. However, increasing evidence suggests that NF-κB activity can also be efficiently contained by direct ubiquitination of NF-κB subunits. Here, we identify the HECT-domain ubiquitin ligase HERC3 as novel negative regulator of NF-κB activity. We find that HERC3 restricts NF-κB nuclear import and DNA binding without affecting IκBα degradation. Instead HERC3 indirectly binds to the NF-κB RelA subunit after liberation from IκBα inhibitor leading to its ubiquitination and protein destabilization. Remarkably, the regulation of RelA activity by HERC3 is independent of its inherent ubiquitin ligase activity. Rather, we show that HERC3 and RelA are part of a multi-protein complex containing the proteasome as well as the ubiquitin-like protein ubiquilin-1 (UBQLN1). We present evidence that HERC3 and UBQLN1 provide a link between NF-κB RelA and the 26S proteasome, thereby facilitating RelA protein degradation. Our findings establish HERC3 as novel candidate regulating the inflammatory response initiated by NF-κB.American Heart Association Scientist Development: (SDG102600298), National Institute of Health
Grants: (HL077308, NS34179), Funding for open access charge: NIH (NS34179)
Modularity and the spread of perturbations in complex dynamical systems
Get PDFWe propose a method to decompose dynamical systems based on the idea that
modules constrain the spread of perturbations. We find partitions of system
variables that maximize 'perturbation modularity', defined as the
autocovariance of coarse-grained perturbed trajectories. The measure
effectively separates the fast intramodular from the slow intermodular dynamics
of perturbation spreading (in this respect, it is a generalization of the
'Markov stability' method of network community detection). Our approach
captures variation of modular organization across different system states, time
scales, and in response to different kinds of perturbations: aspects of
modularity which are all relevant to real-world dynamical systems. It offers a
principled alternative to detecting communities in networks of statistical
dependencies between system variables (e.g., 'relevance networks' or
'functional networks'). Using coupled logistic maps, we demonstrate that the
method uncovers hierarchical modular organization planted in a system's
coupling matrix. Additionally, in homogeneously-coupled map lattices, it
identifies the presence of self-organized modularity that depends on the
initial state, dynamical parameters, and type of perturbations. Our approach
offers a powerful tool for exploring the modular organization of complex
dynamical systems.NSF IGERT fellowship, FLAD Computational Biology Collaboratorium
The Major Facilitator Superfamily Transporter ZIFL2 Modulates Cesium and Potassium Homeostasis in Arabidopsis
Get PDFPotassium (K(+)) is an essential mineral nutrient for plant growth and development, with numerous membrane transporters and channels having been implicated in the maintenance and regulation of its homeostasis. The cation cesium (Cs(+)) is toxic for plants but shares similar chemical properties to the K(+) ion and hence competes with its transport. Here, we report that K(+) and Cs(+) homeostasis in Arabidopsis thaliana also requires the action of ZIFL2 (Zinc-Induced Facilitator-Like 2), a member of the Major Facilitator Superfamily (MFS) of membrane transporters. We show that the Arabidopsis ZIFL2 is a functional transporter able to mediate K(+) and Cs(+) influx when heterologously expressed in yeast. Promoter-reporter, reverse transcription-PCR and fluorescent protein fusion experiments indicate that the predominant ZIFL2.1 isoform is targeted to the plasma membrane of endodermal and pericyle root cells. ZIFL2 loss of function and overexpression exacerbate and alleviate plant sensitivity, respectively, upon Cs(+) and excess K(+) supply, also influencing Cs(+) whole-plant partitioning. We propose that the activity of this Arabidopsis MFS carrier promotes cellular K(+) efflux in the root, thereby restricting Cs(+)/K(+) xylem loading and subsequent root to shoot translocation under conditions of Cs(+) or high K(+) external supply.FCT fellowships: (SFRH/BPD/44640/2008, SFRH/BPD/81221/2011)