When the human viral infectome and diseasome networks collide: towards a systems biology platform for the aetiology of human diseases

<p>Abstract</p> <p>Background</p> <p>Comprehensive understanding of molecular mechanisms underlying viral infection is a major challenge towards the discovery of new antiviral drugs and susceptibility factors of human diseases. New advances in the field are expected from systems-level modelling and integration of the incessant torrent of high-throughput "-omics" data.</p> <p>Results</p> <p>Here, we describe the Human Infectome protein interaction Network, a novel systems virology model of a virtual virus-infected human cell concerning 110 viruses. This <it>in silico </it>model was applied to comprehensively explore the molecular relationships between viruses and their associated diseases. This was done by merging virus-host and host-host physical protein-protein interactomes with the set of genes essential for viral replication and involved in human genetic diseases. This systems-level approach provides strong evidence that viral proteomes target a wide range of functional and inter-connected modules of proteins as well as highly central and bridging proteins within the human interactome. The high centrality of targeted proteins was correlated to their essentiality for viruses' lifecycle, using functional genomic RNAi data. A stealth-attack of viruses on proteins bridging cellular functions was demonstrated by simulation of cellular network perturbations, a property that could be essential in the molecular aetiology of some human diseases. Networking the Human Infectome and Diseasome unravels the connectivity of viruses to a wide range of diseases and profiled molecular basis of Hepatitis C Virus-induced diseases as well as 38 new candidate genetic predisposition factors involved in type 1 <it>diabetes mellitus</it>.</p> <p>Conclusions</p> <p>The Human Infectome and Diseasome Networks described here provide a unique gateway towards the comprehensive modelling and analysis of the systems level properties associated to viral infection as well as candidate genes potentially involved in the molecular aetiology of human diseases.</p

The Interactomes of Influenza Virus NS1 and NS2 Proteins Identify New Host Factors and Provide Insights for ADAR1 Playing a Supportive Role in Virus Replication.

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ETUDE DES MANTEAUX VESICULAIRES IMPLIQUES DANS LE TRANSPORT ENDOCYTIQUE CHEZ L'AMIBE DICTYOSTELIUM DISCOIDEUM (FONCTION PLEIOTROPE DU COMPLEXE AP-1)

LE TRAFIC DES PROTEINES TRANSMEMBRANAIRES ENTRE LES COMPARTIMENTS DES VOIES DE L'ENDOCYTOSE ET DE LA SECRETION EST REALISE PAR DES VESICULES DE TRANSPORT. LA GENESE DE CES VESICULES, DE MEME QUE LA SELECTION DES PROTEINES A TRANSPORTER SONT DEPENDANTES DE PROTEINES DE MANTEAU QUI RECOUVRENT LA SURFACE DES VESICULES DE TRANSPORT. L'UNE DE CES PROTEINES DE MANTEAU, LA CLATHRINE, S'ASSOCIE A DES COMPLEXES PROTEIQUES ADAPTATEURS (AP-1 A AP-4 CHEZ LES EUCARYOTES SUPERIEURS). CES COMPLEXES AP PERMETTENT LA SPECIFICITE DE RECONNAISSANCE DE MOTIFS DE TRIAGE SITUES SUR LE DOMAINE CYTOPLASMIQUE DES PROTEINES TRANSMEMBRANAIRES. CES MOTIFS SONT DES SEQUENCES DE QUATRE A SIX AMINO ACIDES PRESENTANT UNE TYROSINE ET UN RESIDU HYDROPHOBE EN Y + 3, OU DEUX LEUCINES CONSECUTIVES. LE TRAVAIL PRESENTE ICI A CONSISTE A CARACTERISER ET DEVELOPPER UN NOUVEAU MODELE CELLULAIRE POUR L'ETUDE DU TRAFIC DES PROTEINES TRANSMEMBRANAIRES : L'AMIBE SOCIALE DICTYOSTELIUM DISCOIDEUM. L'IDENTIFICATION DES SOUS-UNITES DES COMPLEXES AP, ET LA CAPACITE DES SIGNAUX DILEUCINE ET TYROSINE A INDUIRE L'ENDOCYTOSE DE RECEPTEURS SUGGERENT QUE LA MACHINERIE DU TRAFIC DES PROTEINES TRANSMEMBRANAIRES CHEZ DICTYOSTELIUM EST COMPARABLE A CELLE DES CELLULES DE MAMMIFERES. NOUS AVONS PU METTRE A PROFIT CE MODELE POUR ETUDIER LA VOIE DE TRANSPORT AP1 DEPENDANTE. L'INACTIVATION DU GENE DE LA CHAINE 1 AFFECTE L'ENDOCYTOSE DE PHASE FLUIDE ET LA PHAGOCYTOSE, LE TRIAGE DES PRECURSEURS D'ENZYMES LYSOSOMALES DE L'APPAREIL DE GOLGI VERS LES LYSOSOMES, LA SECRETION D'HYDROLASES MATURES DES LYSOSOMES VERS LE MILIEU EXTRACELLULAIRE ET L'EXOCYTOSE DE LA PHASE FLUIDE. L'ENDOCYTOSE DE RECEPTEUR NE SEMBLE PAS ETRE AFFECTEE PAR L'ABSENCE DE CHAINE 1. CES RESULTATS SUGGERENT QUE LE COMPLEXE AP1 POURRAIT CONTROLER PLUSIEURS VOIES DE TRANSPORT INTRACELLULAIRE.LYON1-BU.Sciences (692662101) / SudocSudocFranceF

Virus-host interactomics: new insights and opportunities for antiviral drug discovery

International audienceThe current therapeutic arsenal against viral infections remains limited, with often poor efficacy and incomplete coverage, and appears inadequate to face the emergence of drug resistance. Our understanding of viral biology and pathophysiology and our ability to develop a more effective antiviral arsenal would greatly benefit from a more comprehensive picture of the events that lead to viral replication and associated symptoms. Towards this goal, the construction of virus-host interactomes is instrumental, mainly relying on the assumption that a viral infection at the cellular level can be viewed as a number of perturbations introduced into the host protein network when viral proteins make new connections and disrupt existing ones. Here, we review advances in interactomic approaches for viral infections, focusing on high-throughput screening (HTS) technologies and on the generation of high-quality datasets. We show how these are already beginning to offer intriguing perspectives in terms of virus-host cell biology and the control of cellular functions, and we conclude by offering a summary of the current situation regarding the potential development of host-oriented antiviral therapeutics

pISTil: a pipeline for yeast two-hybrid Interaction Sequence Tags identification and analysis.

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Calcineurin A vs NS5A-TP2/HDDC2: a case study of site-directed low-frequency random mutagenesis for dissecting target specificity of peptide aptamers

We have previously identified a peptide aptamer (named "R5G42") via functional selection, for its capacity to slow cell proliferation. A yeast two-hybrid screen of human cDNA libraries, using R5G42 as "bait", allowed identification of two binding proteins with very different functions: Calcineurin A (CnA) (PP2B/PPP3CA), a protein phosphatase well characterized e.g. for its role in the immune response, and NS5A-TP2/HDDC2, a much less studied protein, induced subsequent to Hepatitis C virus Non-structural protein 5A expression in HepG2 hepatocellular carcinoma cells, with no known activity. Our objective, in the present study, was to dissect the dual target specificity of R5G42 in order to have tools with which to be able to better characterize the actions of the peptide aptamers towards their individual targets. This was achieved by the selection of random mutants of the variable loop, derived from R5G42, evaluating their specificity towards CnA and NS5A-TP2, and analyzing their sequence. An interdisciplinary approach, involving biomolecular computer simulations with integration of the sequence data and yeast two hybrid binding phenotypes of these mutants, yielded two structurally-distinct conformers affording the potential molecular basis of the binding diversity of R5G42. Evaluation of the biological impact of CnA- vs NS5A-TP2-specific peptide aptamers indicated that, while both contributed to the anti-proliferative effect of R5G42, CnA-binding was essential to stimulate nuclear translocation of NFAT, indicative of activation of endogenous CnA. By dissecting target specificity of R5G42, we have generated novel tools with which to study each target individually. Apta-C8 is capable of directly activating CnA independently of binding to NS5A-TP2 and will be an important tool to study the role of CnA activation in the regulation of different signalling pathways, whereas Apta-E1 will allow dissection of the function of NS5A-TP2, serving as an example of the usefulness of peptide aptamer technology for investigating signaling pathways

An anti-diabetic drug targets NEET (CISD) proteins through destabilization of their [2Fe-2S] clusters

Elevated levels of mitochondrial iron and reactive oxygen species (ROS) accompany the progression of diabetes, negatively impacting insulin production and secretion from pancreatic cells. In search for a tool to reduce mitochondrial iron and ROS levels, we arrived at a molecule that destabilizes the [2Fe-2S] clusters of NEET proteins (M1). Treatment of db/db diabetic mice with M1 improved hyperglycemia, without the weight gain observed with alternative treatments such as rosiglitazone. The molecular interactions of M1 with the NEET proteins mNT and NAF-1 were determined by X-crystallography. The possibility of controlling diabetes by molecules that destabilize the [2Fe–2S] clusters of NEET proteins, thereby reducing iron-mediated oxidative stress, opens a new route for managing metabolic aberration such as in diabetes

Mitochondrial morphodynamics alteration induced by influenza virus infection as a new antiviral strategy.

Influenza virus infections are major public health threats due to their high rates of morbidity and mortality. Upon influenza virus entry, host cells experience modifications of endomembranes, including those used for virus trafficking and replication. Here we report that influenza virus infection modifies mitochondrial morphodynamics by promoting mitochondria elongation and altering endoplasmic reticulum-mitochondria tethering in host cells. Expression of the viral RNA recapitulates these modifications inside cells. Virus induced mitochondria hyper-elongation was promoted by fission associated protein DRP1 relocalization to the cytosol, enhancing a pro-fusion status. We show that altering mitochondrial hyper-fusion with Mito-C, a novel pro-fission compound, not only restores mitochondrial morphodynamics and endoplasmic reticulum-mitochondria contact sites but also dramatically reduces influenza replication. Finally, we demonstrate that the observed Mito-C antiviral property is directly connected with the innate immunity signaling RIG-I complex at mitochondria. Our data highlight the importance of a functional interchange between mitochondrial morphodynamics and innate immunity machineries in the context of influenza viral infection