Mapping Protein Interactions between Dengue Virus and Its Human and Insect Hosts

Background Dengue fever is an increasingly significant arthropod-borne viral disease, with at least 50 million cases per year worldwide. As with other viral pathogens, dengue virus is dependent on its host to perform the bulk of functions necessary for viral survival and replication. To be successful, dengue must manipulate host cell biological processes towards its own ends, while avoiding elimination by the immune system. Protein-protein interactions between the virus and its host are one avenue through which dengue can connect and exploit these host cellular pathways and processes. Methodology/Principal Findings We implemented a computational approach to predict interactions between Dengue virus (DENV) and both of its hosts, Homo sapiens and the insect vector Aedes aegypti. Our approach is based on structural similarity between DENV and host proteins and incorporates knowledge from the literature to further support a subset of the predictions. We predict over 4,000 interactions between DENV and humans, as well as 176 interactions between DENV and A. aegypti. Additional filtering based on shared Gene Ontology cellular component annotation reduced the number of predictions to approximately 2,000 for humans and 18 for A. aegypti. Of 19 experimentally validated interactions between DENV and humans extracted from the literature, this method was able to predict nearly half (9). Additional predictions suggest specific interactions between virus and host proteins relevant to interferon signaling, transcriptional regulation, stress, and the unfolded protein response. Conclusions/Significance Dengue virus manipulates cellular processes to its advantage through specific interactions with the host's protein interaction network. The interaction networks presented here provide a set of hypothesis for further experimental investigation into the DENV life cycle as well as potential therapeutic targets.

[1]  Xiaoqun Duan,et al.  Polypyrimidine tract-binding protein influences negative strand RNA synthesis of dengue virus , 2009, Biochemical and Biophysical Research Communications.

[2]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[3]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[4]  Subhash G. Vasudevan,et al.  Structure of the Dengue Virus Helicase/Nucleoside Triphosphatase Catalytic Domain at a Resolution of 2.4 Å , 2005, Journal of Virology.

[5]  Adolfo García-Sastre,et al.  Inhibition of interferon signaling by dengue virus , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Hui Lu,et al.  MULTIPROSPECTOR: An algorithm for the prediction of protein–protein interactions by multimeric threading , 2002, Proteins.

[7]  D. Smith,et al.  Identification of GRP 78 (BiP) as a liver cell expressed receptor element for dengue virus serotype 2 , 2004, Archives of Virology.

[8]  Shui-Tein Chen,et al.  Proteomic analysis of host responses in HepG2 cells during dengue virus infection. , 2007, Journal of proteome research.

[9]  Narayanan Eswar,et al.  Host–pathogen protein interactions predicted by comparative modeling , 2007, Protein science : a publication of the Protein Society.

[10]  W. Delano.  The PyMOL Molecular Graphics System , 2002 .

[11]  C. van Hoof,et al.  PP2A: the expected tumor suppressor. , 2005, Current opinion in genetics & development.

[12]  Madeline A. Crosby,et al.  FlyBase: genomes by the dozen , 2006, Nucleic Acids Res..

[13]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[14]  C. Thepparit,et al.  Serotype-Specific Entry of Dengue Virus into Liver Cells: Identification of the 37-Kilodalton/67-Kilodalton High-Affinity Laminin Receptor as a Dengue Virus Serotype 1 Receptor , 2004, Journal of Virology.

[15]  S. H. Wang,et al.  The heterogeneous nuclear ribonucleoprotein K (hnRNP K) interacts with dengue virus core protein. , 2001, DNA and cell biology.

[16]  Erik L. L. Sonnhammer,et al.  InParanoid 6: eukaryotic ortholog clusters with inparalogs , 2007, Nucleic Acids Res..

[17]  N. Shafee,et al.  Dengue virus type 2 NS3 protease and NS2B-NS3 protease precursor induce apoptosis. , 2003, The Journal of general virology.

[18]  Shui-Tein Chen,et al.  Identification of human hnRNP C1/C2 as a dengue virus NS1-interacting protein. , 2008, Biochemical and biophysical research communications.

[19]  Richard J Kuhn,et al.  Structural proteomics of dengue virus. , 2008, Current opinion in microbiology.

[20]  E. Chevet,et al.  Dengue virus serotype infection specifies the activation of the unfolded protein response , 2007, Virology Journal.

[21]  P. Mhawech,et al.  14-3-3 proteins—an update , 2005, Cell Research.

[22]  H. Shih,et al.  The type 2 dengue virus envelope protein interacts with small ubiquitin-like modifier-1 (SUMO-1) conjugating enzyme 9 (Ubc9). , 2007, Journal of biomedical science.

[23]  C. Hack,et al.  Activation of coagulation factor XI, without detectable contact activation in dengue haemorrhagic fever , 2001, British journal of haematology.

[24]  S. Higgs,et al.  Ultrastructural Study of West Nile Virus Pathogenesis in Culex pipiens quinquefasciatus (Diptera: Culicidae) , 2005, Journal of medical entomology.

[25]  Liisa Holm,et al.  Searching protein structure databases with DaliLite v.3 , 2008, Bioinform..

[26]  R. D. del Ángel,et al.  La protein binds to NS5 and NS3 and to the 5' and 3' ends of Dengue 4 virus RNA. , 2004, Virus research.

[27]  I. Sánchez-Vargas,et al.  RNA interference, arthropod-borne viruses, and mosquitoes. , 2004, Virus research.

[28]  Guozhen Liu,et al.  DroID: the Drosophila Interactions Database, a comprehensive resource for annotated gene and protein interactions , 2008, BMC Genomics.

[29]  R. D. del Ángel,et al.  Heat Shock Protein 90 and Heat Shock Protein 70 Are Components of Dengue Virus Receptor Complex in Human Cells , 2005, Journal of Virology.

[30]  M. Garcia-Blanco,et al.  Discovery of Insect and Human Dengue Virus Host Factors , 2009, Nature.

[31]  V. Chow,et al.  The non-structural 3 (NS3) protein of dengue virus type 2 interacts with human nuclear receptor binding protein and is associated with alterations in membrane structure. , 2004, Virus research.

[32]  J. Mackenzie,et al.  Dengue virus binding to human leukocyte cell lines: receptor usage differs between cell types and virus strains. , 2001, Virus research.

[33]  M. Johansson,et al.  Flavivirus NS5 associates with host-cell proteins zonula occludens-1 (ZO-1) and regulating synaptic membrane exocytosis-2 (RIMS2) via an internal PDZ binding mechanism , 2009, Biological chemistry.

[34]  K. Ikuta,et al.  Secreted complement regulatory protein clusterin interacts with dengue virus nonstructural protein 1. , 2007, Biochemical and biophysical research communications.

[35]  Cathy H. Wu,et al.  The Universal Protein Resource (UniProt) , 2004, Nucleic Acids Res..

[36]  Structure of a type II thymidine kinase with bound dTTP , 2005, FEBS letters.

[37]  A. Nisalak,et al.  High levels of interferon alpha in the sera of children with dengue virus infection. , 1993, The American journal of tropical medicine and hygiene.

[38]  P. Desprès,et al.  Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN)-mediated Enhancement of Dengue Virus Infection Is Independent of DC-SIGN Internalization Signals* , 2005, Journal of Biological Chemistry.

[39]  R. Kaufman,et al.  The unfolded protein response , 2003, Journal of Cell Science.

[40]  A. Kroeger,et al.  Dengue: setting the global research agenda , 2006, The Lancet.

[41]  P. Yenchitsomanus,et al.  Sensitization to Fas-mediated apoptosis by dengue virus capsid protein. , 2007, Biochemical and biophysical research communications.

[42]  Matthew D. Dyer,et al.  The Landscape of Human Proteins Interacting with Viruses and Other Pathogens , 2008, PLoS pathogens.

[43]  Tom L. Blundell,et al.  Insights into DNA recombination from the structure of a RAD51–BRCA2 complex , 2002, Nature.

[44]  R. D. del Ángel,et al.  Mosquito La protein binds to the 3' untranslated region of the positive and negative polarity dengue virus RNAs and relocates to the cytoplasm of infected cells. , 2007, Virology.

[45]  D. R. Taylor,et al.  Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. , 1999, Science.

[46]  Shawn M Gomez,et al.  Structural similarity-based predictions of protein interactions between HIV-1 and Homo sapiens , 2010, Virology Journal.

[47]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[48]  G. Dimopoulos,et al.  An evolutionary conserved function of the JAK-STAT pathway in anti-dengue defense , 2009, Proceedings of the National Academy of Sciences.

[49]  M. Ramanathan,et al.  Host cell killing by the West Nile Virus NS2B-NS3 proteolytic complex: NS3 alone is sufficient to recruit caspase-8-based apoptotic pathway. , 2006, Virology.

[50]  A. Falconar,et al.  The dengue virus nonstructural-1 protein (NS1) generatesantibodies to common epitopes on human blood clotting,integrin/adhesin proteins and binds to humanendothelial cells: potential implications in haemorrhagic fever pathogenesis , 1997, Archives of Virology.

[51]  M. Diamond,et al.  Interferon inhibits dengue virus infection by preventing translation of viral RNA through a PKR-independent mechanism. , 2001, Virology.

[52]  T. M. Murali,et al.  Computational prediction of host-pathogen protein-protein interactions , 2007, ISMB/ECCB.

[53]  K. Mori,et al.  Endoplasmic Reticulum Stress-Induced Formation of Transcription Factor Complex ERSF Including NF-Y (CBF) and Activating Transcription Factors 6α and 6β That Activates the Mammalian Unfolded Protein Response , 2001, Molecular and Cellular Biology.

[54]  Erkang Wang,et al.  Uncovering the rules for protein–protein interactions from yeast genomic data , 2009, Proceedings of the National Academy of Sciences.

[55]  Yanjun Qi,et al.  Prediction of Interactions Between HIV-1 and Human Proteins by Information Integration , 2008, Pacific Symposium on Biocomputing.

[56]  Donna R. Maglott,et al.  Human immunodeficiency virus type 1, human protein interaction database at NCBI , 2008, Nucleic Acids Res..

[57]  D. Chang,et al.  Dengue virus type 2 antagonizes IFN-alpha but not IFN-gamma antiviral effect via down-regulating Tyk2-STAT signaling in the human dendritic cell. , 2005, Journal of immunology.

[58]  Rafael C. Jimenez,et al.  The IntAct molecular interaction database in 2012 , 2011, Nucleic Acids Res..

[59]  P. Yenchitsomanus,et al.  Interaction of dengue virus envelope protein with endoplasmic reticulum-resident chaperones facilitates dengue virus production. , 2009, Biochemical and biophysical research communications.

[60]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[61]  Michael G. Katze,et al.  Control of PKR Protein Kinase by Hepatitis C Virus Nonstructural 5A Protein: Molecular Mechanisms of Kinase Regulation , 1998, Molecular and Cellular Biology.

[62]  H. Chee,et al.  Identification of a 48 kDa tubulin or tubulin-like C6/36 mosquito cells protein that binds dengue virus 2 using mass spectrometry , 2004 .

[63]  M. Ng,et al.  Recombinant non-structural 1 (NS1) protein of dengue-2 virus interacts with human STAT3beta protein. , 2005, Virus research.

[64]  Yigong Shi,et al.  Structure of the apoptotic protease-activating factor 1 bound to ADP , 2005, Nature.

[65]  M. Salas-Benito,et al.  Evidence that the 45-kD glycoprotein, part of a putative dengue virus receptor complex in the mosquito cell line C6/36, is a heat-shock related protein. , 2007, The American journal of tropical medicine and hygiene.

[66]  Yi-Ling Lin,et al.  Flavivirus Infection Activates the XBP1 Pathway of the Unfolded Protein Response To Cope with Endoplasmic Reticulum Stress , 2006, Journal of Virology.

[67]  Robert B. Russell,et al.  InterPreTS: protein Interaction Prediction through Tertiary Structure , 2003, Bioinform..

[68]  Cheng-Yan Kao,et al.  Ortholog-based protein-protein interaction prediction and its application to inter-species interactions , 2008, BMC Bioinformatics.

[69]  P. Desprès,et al.  Determinants in the envelope E protein and viral RNA helicase NS3 that influence the induction of apoptosis in response to infection with dengue type 1 virus. , 2000, Virology.

[70]  D. Vaughn,et al.  Impact of dengue virus infection on feeding behavior of Aedes aegypti. , 1997, The American journal of tropical medicine and hygiene.

[71]  G. Foster,et al.  Dengue Virus Inhibits Alpha Interferon Signaling by Reducing STAT2 Expression , 2005, Journal of Virology.

[72]  Lyle Ungar,et al.  Prediction of HIV-1 virus-host protein interactions using virus and host sequence motifs , 2009, BMC Medical Genomics.

[73]  C. Sander,et al.  Protein structure comparison by alignment of distance matrices. , 1993, Journal of molecular biology.

[74]  Haruki Nakamura,et al.  Announcing the worldwide Protein Data Bank , 2003, Nature Structural Biology.

[75]  Ursula Pieper,et al.  Protein complex compositions predicted by structural similarity , 2006, Nucleic acids research.

[76]  C. King,et al.  Bacterial Lipopolysaccharide Inhibits Dengue Virus Infection of Primary Human Monocytes/Macrophages by Blockade of Virus Entry via a CD14-Dependent Mechanism , 1999, Journal of Virology.

[77]  Z. Xi,et al.  Response of the mosquito protein interaction network to dengue infection , 2010, BMC Genomics.

[78]  S. Nimmannitya,et al.  Haematology in dengue and dengue haemorrhagic fever. , 2000, Bailliere's best practice & research. Clinical haematology.

[79]  Sameer Velankar,et al.  E-MSD: improving data deposition and structure quality , 2005, Nucleic Acids Res..

[80]  Zhiyong Xi,et al.  The Aedes aegypti Toll Pathway Controls Dengue Virus Infection , 2008, PLoS pathogens.

[81]  Pei-Yong Shi,et al.  NS5 of Dengue Virus Mediates STAT2 Binding and Degradation , 2009, Journal of Virology.

[82]  Jing An,et al.  The pathogenesis of spinal cord involvement in dengue virus infection , 2003, Virchows Archiv.

[83]  M. Hibberd,et al.  Dengue virus regulates type I interferon signalling in a strain-dependent manner in human cell lines. , 2008, The Journal of general virology.

[84]  Liisa Holm,et al.  Evaluation of different domain-based methods in protein interaction prediction. , 2009, Biochemical and biophysical research communications.

[85]  Ruth R. Montgomery,et al.  RNA interference screen for human genes associated with West Nile virus infection , 2008, Nature.

[86]  Nan Wang,et al.  AgBase: a functional genomics resource for agriculture , 2006, BMC Genomics.

[87]  Yang Zhang,et al.  I-TASSER server for protein 3D structure prediction , 2008, BMC Bioinformatics.