Send Orders of Reprints at Bspsaif@emirates.net.ae the Hpv E2-host Protein-protein Interactions: a Complex Hijacking of the Cellular Network

Over 100 genotypes of human papillomaviruses (HPVs) have been identified as being responsible for unapparent infections or for lesions ranging from benign skin or genital warts to cancer. The pathogenesis of HPV results from complex relationships between viral and host factors, driven in particular by the interplay between the host proteome and the early viral proteins. The E2 protein regulates the transcription, the replication as well as the mitotic segregation of the viral genome through the recruitment of host cell factors to the HPV regulatory region. It is thereby a pivotal factor for the productive viral life cycle and for viral persistence, a major risk factor for cancer development. In addition, the E2 proteins have been shown to engage numerous interactions through which they play important roles in modulating the host cell. Such E2 activities are probably contributing to create cell conditions appropriate for the successive stages of the viral life cycle, and some of these activities have been demonstrated only for the oncogenic high-risk HPV. The recent mapping of E2-host protein-protein interactions with 12 genotypes representative of HPV diversity has shed some light on the large complexity of the host cell hijacking and on its diversity according to viral genotypes. This article reviews the functions of E2 as they emerge from the E2/host proteome interplay, taking into account the large-scale comparative interactomic study.

[1]  L. Chow,et al.  Human papillomavirus type 11 E2 proteins repress the homologous E6 promoter by interfering with the binding of host transcription factors to adjacent elements , 1994, Journal of virology.

[2]  J. Champoux.  DNA topoisomerases: structure, function, and mechanism. , 2001, Annual review of biochemistry.

[3]  J. McDonald.  Extracellular matrix assembly. , 1988, Annual review of cell biology.

[4]  F. Thierry,et al.  Tumor suppressor or oncogene? A critical role of the human papillomavirus (HPV) E2 protein in cervical cancer progression. , 2011, American journal of cancer research.

[5]  L. Shulman.  Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression , 2010 .

[6]  D. Lowy,et al.  Efficient Intracellular Assembly of Papillomaviral Vectors , 2004, Journal of Virology.

[7]  R. Tjian,et al.  Direct interaction between Sp1 and the BPV enhancer E2 protein mediates synergistic activation of transcription , 1991, Cell.

[8]  J. G. Oliveira,et al.  Partitioning Viral Genomes in Mitosis: Same Idea, Different Targets , 2006, Cell cycle.

[9]  John Calvin Reed,et al.  Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. , 2000, Science.

[10]  P. Stern,et al.  The Human Papillomavirus (HPV) 16 E2 Protein Induces Apoptosis in the Absence of Other HPV Proteins and via a p53-dependent Pathway* , 2000, The Journal of Biological Chemistry.

[11]  B. Berger,et al.  Herpesviral Protein Networks and Their Interaction with the Human Proteome , 2006, Science.

[12]  B. Akgül,et al.  The human papillomavirus type 8 E2 protein induces skin tumors in transgenic mice. , 2008, The Journal of investigative dermatology.

[13]  J. Choe,et al.  Functional Interaction between p/CAF and Human Papillomavirus E2 Protein* , 2002, The Journal of Biological Chemistry.

[14]  Norman E. Davey,et al.  How viruses hijack cell regulation. , 2011, Trends in biochemical sciences.

[15]  Aaron Ciechanover,et al.  The HECT family of E3 ubiquitin ligases: multiple players in cancer development. , 2008, Cancer cell.

[16]  W. Leonard,et al.  Functional Association of Nmi with Stat5 and Stat1 in IL-2- and IFN γ-Mediated Signaling , 1999, Cell.

[17]  G. Dreyfuss,et al.  The SMN–SIP1 Complex Has an Essential Role in Spliceosomal snRNP Biogenesis , 1997, Cell.

[18]  R. Pfuetzner,et al.  Crystal Structure of the DNA-Binding Domain of the Epstein–Barr Virus Origin-Binding Protein, EBNA1, Bound to DNA , 1996, Cell.

[19]  B. Goud,et al.  Interaction of a Golgi-associated kinesin-like protein with Rab6. , 1998, Science.

[20]  J. Archambault,et al.  Small Molecule Inhibitors of Human Papillomavirus Protein - Protein Interactions , 2011, The open virology journal.

[21]  A. Fassati,et al.  Transportin 3 Promotes a Nuclear Maturation Step Required for Efficient HIV-1 Integration , 2011, PLoS pathogens.

[22]  K. Wilson,et al.  Structure of the intact transactivation domain of the human papillomavirus E2 protein , 2000, Nature.

[23]  Y. Pommier,et al.  Topoisomerase II and tubulin inhibitors both induce the formation of apoptotic topoisomerase I cleavage complexes , 2006, Molecular Cancer Therapeutics.

[24]  K. Abromeit.  Music Received , 2023, Notes.

[25]  S. Graham,et al.  Human Papillomavirus Type 16 E2 Protein Transcriptionally Activates the Promoter of a Key Cellular Splicing Factor, SF2/ASF , 2008, Journal of Virology.

[26]  Trey Ideker,et al.  Cytoscape 2.8: new features for data integration and network visualization , 2010, Bioinform..

[27]  J. Kere,et al.  The CCHCR1 (HCR) gene is relevant for skin steroidogenesis and downregulated in cultured psoriatic keratinocytes , 2007, Journal of Molecular Medicine.

[28]  F. Stubenrauch,et al.  Low-affinity E2-binding site mediates downmodulation of E2 transactivation of the human papillomavirus type 8 late promoter , 1994, Journal of virology.

[29]  J. D. Benson,et al.  Conserved interaction of the papillomavirus E2 transcriptional activator proteins with human and yeast TFIIB proteins , 1997, Journal of virology.

[30]  A. Vazquez,et al.  Epstein–Barr virus and virus human protein interaction maps , 2007, Proceedings of the National Academy of Sciences.

[31]  John Calvin Reed,et al.  Conversion of Bcl-2 from Protector to Killer by Interaction with Nuclear Orphan Receptor Nur77/TR3 , 2004, Cell.

[32]  P. Howley,et al.  The functional BPV-1 E2 trans-activating protein can act as a repressor by preventing formation of the initiation complex. , 1991, Genes & development.

[33]  H. Pfister,et al.  The Human Papillomavirus Type 8 E2 Protein Suppresses β4-Integrin Expression in Primary Human Keratinocytes , 2004, Journal of Virology.

[34]  R. Tjian,et al.  TBP-TAF complexes: selectivity factors for eukaryotic transcription. , 1994, Current opinion in cell biology.

[35]  J. Comella,et al.  A new model to study spinal muscular atrophy: Neurite degeneration and cell death is counteracted by BCL-XL Overexpression in motoneurons , 2011, Neurobiology of Disease.

[36]  D. Soprano,et al.  Comparison of the mechanism of induction of apoptosis in ovarian carcinoma cells by the conformationally restricted synthetic retinoids CD437 and 4‐HPR , 2003, Journal of cellular biochemistry.

[37]  D. Chakravarti,et al.  Novel regulatory role for human Acf1 in transcriptional repression of vitamin D3 receptor-regulated genes. , 2007, Molecular endocrinology.

[38]  M. McFarlane,et al.  Human papillomavirus regulation of SR proteins. , 2010, Biochemical Society transactions.

[39]  P. Gariglio,et al.  Early promoters of genital and cutaneous human papillomaviruses are differentially regulated by the bovine papillomavirus type 1 E2 gene product. , 1992, The Journal of general virology.

[40]  M. Yaniv,et al.  Cooperative activation of transcription by bovine papillomavirus type 1 E2 can occur over a large distance , 1990, Molecular and cellular biology.

[41]  Shwu‐Yuan Wu,et al.  The Double Bromodomain-containing Chromatin Adaptor Brd4 and Transcriptional Regulation* , 2007, Journal of Biological Chemistry.

[42]  Guo-Jun Zhang,et al.  Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex , 2004, Nature.

[43]  Qing-quan Li,et al.  RACK1 promotes breast carcinoma migration/metastasis via activation of the RhoA/Rho kinase pathway , 2011, Breast Cancer Research and Treatment.

[44]  S. Tsukita,et al.  Functional involvement of TMF/ARA160 in Rab6-dependent retrograde membrane traffic. , 2007, Experimental cell research.

[45]  M. Lai,et al.  A Human Papillomavirus E2 Transcriptional Activator , 1999, The Journal of Biological Chemistry.

[46]  M. Ptashne,et al.  Transcriptional activation by recruitment , 1997, Nature.

[47]  I. Frazer,et al.  BPV1 E2 protein enhances packaging of full-length plasmid DNA in BPV1 pseudovirions. , 2000, Virology.

[48]  E. Rybicki,et al.  Insights into the role and function of L2, the minor capsid protein of papillomaviruses , 2009, Archives of Virology.

[49]  Y. Xiong,et al.  Targeting of protein ubiquitination by BTB–Cullin 3–Roc1 ubiquitin ligases , 2003, Nature Cell Biology.

[50]  M. Botchan,et al.  Structure of the papillomavirus DNA-tethering complex E2:Brd4 and a peptide that ablates HPV chromosomal association. , 2006, Molecular cell.

[51]  B. Akgül,et al.  The E2 protein of human papillomavirus type 8 increases the expression of matrix metalloproteinase-9 in human keratinocytes and organotypic skin cultures , 2011, Medical Microbiology and Immunology.

[52]  M. Vidal,et al.  Hepatitis C virus infection protein network , 2008, Molecular systems biology.

[53]  K. Münger,et al.  The Cytokines Tumor Necrosis Factor-α (TNF-α) and TNF-related Apoptosis-inducing Ligand Differentially Modulate Proliferation and Apoptotic Pathways in Human Keratinocytes Expressing the Human Papillomavirus-16 E7 Oncoprotein* , 2001, The Journal of Biological Chemistry.

[54]  C. Demeret,et al.  Direct activation of caspase 8 by the proapoptotic E2 protein of HPV18 independent of adaptor proteins , 2008, Cell Death and Differentiation.

[55]  B. Calnan,et al.  Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas , 1994, Nature.

[56]  D. Rotin,et al.  Physiological functions of the HECT family of ubiquitin ligases , 2009, Nature Reviews Molecular Cell Biology.

[57]  Yifan Cheng,et al.  The chromatin remodeler ACF acts as a dimeric motor to space nucleosomes , 2009, Nature.

[58]  K. Choo,et al.  Integration of human papillomavirus type 16 into cellular DNA of cervical carcinoma: preferential deletion of the E2 gene and invariable retention of the long control region and the E6/E7 open reading frames. , 1987, Virology.

[59]  Irene L. Ch’en,et al.  Dynamic expression of epidermal caspase-8 simulates a wound healing response , 2009, Nature.

[60]  Brad T. Sherman,et al.  Extracting Biological Meaning from Large Gene Lists with DAVID , 2009, Current protocols in bioinformatics.

[61]  G. Karpen,et al.  Acf1 confers unique activities to ACF/CHRAC and promotes the formation rather than disruption of chromatin in vivo. , 2004, Genes & development.

[62]  Christopher L. McClendon,et al.  Reaching for high-hanging fruit in drug discovery at protein–protein interfaces , 2007, Nature.

[63]  C. Demeret,et al.  The regulatory E2 proteins of human genital papillomaviruses are pro-apoptotic. , 2003, Biochimie.

[64]  N. Maitland,et al.  Phenotypic effects of HPV-16 E2 protein expression in human keratinocytes. , 2010, Virology.

[65]  E. Garrido,et al.  Specific in vitro Interaction between Papillomavirus E2 Proteins and TBP-Associated Factors , 2004, Intervirology.

[66]  E. Androphy,et al.  ChlR1 is required for loading papillomavirus E2 onto mitotic chromosomes and viral genome maintenance. , 2006, Molecular cell.

[67]  G. Steger,et al.  Cooperative Activation of Human Papillomavirus Type 8 Gene Expression by the E2 Protein and the Cellular Coactivator p300 , 2002, Journal of Virology.

[68]  E. Androphy,et al.  Mitotic Kinesin-Like Protein 2 Binds and Colocalizes with Papillomavirus E2 during Mitosis , 2006, Journal of Virology.

[69]  V. Faundez,et al.  Intermediate Filaments and Vesicular Membrane Traffic: The Odd Couple's First Dance? , 2005, Traffic.

[70]  P. Lambert,et al.  Interaction of the papillomavirus transcription/replication factor, E2, and the viral capsid protein, L2. , 2000, Virology.

[71]  F. Méchali,et al.  High-Risk But Not Low-Risk HPV E2 Proteins Bind to the APC Activators Cdh1 and Cdc20 and Cause Genomic Instability , 2005, Cell cycle.

[72]  Shin-Young Park,et al.  Characterization of the Tyrosine Kinases RAFTK/Pyk2 and FAK in Nerve Growth Factor-induced Neuronal Differentiation* , 2000, The Journal of Biological Chemistry.

[73]  S. Corden,et al.  The integration of HPV-18 DNA in cervical carcinoma. , 1999, Molecular pathology : MP.

[74]  R. Mitra,et al.  Brd4 Is Required for E2-Mediated Transcriptional Activation but Not Genome Partitioning of All Papillomaviruses , 2006, Journal of Virology.

[75]  Takashi Yamamoto,et al.  RSF Governs Silent Chromatin Formation via Histone H2Av Replacement , 2008, PLoS genetics.

[76]  A. Wandinger-Ness,et al.  Caveolin-1-Dependent Infectious Entry of Human Papillomavirus Type 31 in Human Keratinocytes Proceeds to the Endosomal Pathway for pH-Dependent Uncoating , 2008, Journal of Virology.

[77]  M. Yaniv,et al.  ATP-dependent chromatin remodelling: SWI/SNF and Co. are on the job. , 1999, Journal of molecular biology.

[78]  C. Chiang,et al.  Chromatin Adaptor Brd4 Modulates E2 Transcription Activity and Protein Stability* , 2009, Journal of Biological Chemistry.

[79]  Brian T Chait,et al.  The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. , 2002, Molecular cell.

[80]  Y. Jacob,et al.  Large Scale Genotype Comparison of Human Papillomavirus E2-Host Interaction Networks Provides New Insights for E2 Molecular Functions , 2012, PLoS pathogens.

[81]  Leena Latonen,et al.  CCHCR1 Is Up-Regulated in Skin Cancer and Associated with EGFR Expression , 2009, PloS one.

[82]  C. Lorson,et al.  Identification of survival motor neuron as a transcriptional activator-binding protein. , 1999, Human molecular genetics.

[83]  A. Barabasi,et al.  Interactome Networks and Human Disease , 2011, Cell.

[84]  C. Demeret,et al.  Stability of the Human Papillomavirus Type 18 E2 Protein Is Regulated by a Proteasome Degradation Pathway through Its Amino-Terminal Transactivation Domain , 2001, Journal of Virology.

[85]  D. Bruemmer,et al.  NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology. , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[86]  M. Lai,et al.  A Human Importin-β Family Protein, Transportin-SR2, Interacts with the Phosphorylated RS Domain of SR Proteins* , 2000, The Journal of Biological Chemistry.

[87]  G. K. Bilter,et al.  Enhanced transcriptional activation by E2 proteins from the oncogenic human papillomaviruses , 1996, Journal of virology.

[88]  M. Yaniv,et al.  Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes , 1997, Journal of virology.

[89]  Cheng-Ming Chiang,et al.  Transcriptional Activity among High and Low Risk Human Papillomavirus E2 Proteins Correlates with E2 DNA Binding* , 2002, The Journal of Biological Chemistry.

[90]  C. Demeret,et al.  Nucleo-cytoplasmic Shuttling of High Risk Human Papillomavirus E2 Proteins Induces Apoptosis* , 2005, Journal of Biological Chemistry.

[91]  P. Howley,et al.  Interaction of the Bovine Papillomavirus E2 Protein with Brd4 Tethers the Viral DNA to Host Mitotic Chromosomes , 2004, Cell.

[92]  E. Garrido,et al.  HPV16 E2 could act as down-regulator in cellular genes implicated in apoptosis, proliferation and cell differentiation , 2011, Virology Journal.

[93]  J. Choe,et al.  cAMP Response Element-binding Protein-binding Protein Binds to Human Papillomavirus E2 Protein and Activates E2-dependent Transcription* , 2000, The Journal of Biological Chemistry.

[94]  Kevin Gaston,et al.  E2 Proteins from High- and Low-Risk Human Papillomavirus Types Differ in Their Ability To Bind p53 and Induce Apoptotic Cell Death , 2006, Journal of Virology.

[95]  Marcin Schmidt,et al.  Orphan nuclear hormone receptor NR4A1 interacts with HPV16 E2 regulatory protein , 2006, Cellular & Molecular Biology Letters.

[96]  L. Banks,et al.  The Mdm2 Ubiquitin Ligase Enhances Transcriptional Activity of Human Papillomavirus E2 , 2008, Journal of Virology.

[97]  J. Miyoshi,et al.  Cell adhesion molecules nectins and associating proteins: Implications for physiology and pathology , 2010, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[98]  J. Choe,et al.  Functional interaction between human papillomavirus type 18 E2 and poly(ADP-ribose) polymerase 1 , 2002, Oncogene.

[99]  S. Cha,et al.  hSNF5 Is Required for Human Papillomavirus E2-Driven Transcriptional Activation and DNA Replication , 2010, Intervirology.

[100]  G. Steger,et al.  Direct Interaction between Nucleosome Assembly Protein 1 and the Papillomavirus E2 Proteins Involved in Activation of Transcription , 2004, Molecular and Cellular Biology.

[101]  J. Tazi,et al.  A conserved Drosophila transportin-serine/arginine-rich (SR) protein permits nuclear import of Drosophila SR protein splicing factors and their antagonist repressor splicing factor 1. , 2002, Molecular biology of the cell.

[102]  G. Steger,et al.  The hinge region of the human papillomavirus type 8 E2 protein activates the human p21(WAF1/CIP1) promoter via interaction with Sp1. , 2002, The Journal of general virology.

[103]  J. Choe,et al.  BRCA1 associates with human papillomavirus type 18 E2 and stimulates E2-dependent transcription. , 2003, Biochemical and biophysical research communications.

[104]  D. Pim,et al.  Interaction between the HPV-16 E2 transcriptional activator and p53 , 1999, Oncogene.

[105]  D. Pim,et al.  HPV‐16 E2 contributes to induction of HPV‐16 late gene expression by inhibiting early polyadenylation , 2012, The EMBO journal.

[106]  G. Doitsh,et al.  Hepatitis B Virus pX Interacts with HBXAP, a PHD Finger Protein to Coactivate Transcription* , 2002, The Journal of Biological Chemistry.

[107]  E. Garrido,et al.  TAF1 Interacts with and Modulates Human Papillomavirus 16 E2-Dependent Transcriptional Regulation , 2008, Intervirology.

[108]  Moon-Sing Lee,et al.  Interaction between human papillomavirus type 5 E2 and polo‐like kinase 1 , 2009, Journal of medical virology.

[109]  E. Androphy,et al.  Functional interaction of a novel cellular protein with the papillomavirus E2 transactivation domain , 1997, Molecular and cellular biology.

[110]  Marcin Schmidt,et al.  Search for cellular partners of human papillomavirus type 16 E2 protein , 2008, Archives of Virology.

[111]  I. Morgan,et al.  Novel cellular interacting partners of the human papillomavirus 16 transcription/replication factor E2. , 2002, Virus research.

[112]  B. Lim,et al.  Androgen Receptor Interacts with a Novel MYST Protein, HBO1* , 2000, The Journal of Biological Chemistry.

[113]  A. Barabasi,et al.  An empirical framework for binary interactome mapping , 2008, Nature Methods.

[114]  P. Hurlin,et al.  The MAX-interacting transcription factor network. , 2006, Seminars in cancer biology.

[115]  J. Archambault,et al.  Proteasomal Degradation of the Papillomavirus E2 Protein Is Inhibited by Overexpression of Bromodomain-Containing Protein 4 , 2009, Journal of Virology.

[116]  J. Huibregtse,et al.  HPV E6, E6AP and cervical cancer , 2007, BMC Biochemistry.

[117]  M. Pagano,et al.  Role of the SCFSkp2 Ubiquitin Ligase in the Degradation of p21Cip1 in S Phase* , 2003, Journal of Biological Chemistry.

[118]  Matthias Mann,et al.  Chromatin-remodelling factor CHRAC contains the ATPases ISWI and topoisomerase II , 1997, Nature.

[119]  P. He,et al.  The Human Papillomavirus Type 18 E2 Protein Is a Cell Cycle-Dependent Target of the SCFSkp2 Ubiquitin Ligase , 2009, Journal of Virology.

[120]  Yan Hu,et al.  Papillomavirus E2 protein interacts with and stimulates human topoisomerase I. , 2006, Virology.

[121]  E. Androphy,et al.  Tax1BP1 Interacts with Papillomavirus E2 and Regulates E2-Dependent Transcription and Stability , 2008, Journal of Virology.

[122]  K. Gaston,et al.  Comprehensive comparison of the interaction of the E2 master regulator with its cognate target DNA sites in 73 human papillomavirus types by sequence statistics , 2007, Nucleic acids research.

[123]  M. Vidal,et al.  Comparative analysis of virus-host interactomes with a mammalian high-throughput protein complementation assay based on Gaussia princeps luciferase. , 2012, Methods.

[124]  A. Wolffe,et al.  A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2. , 1998, Molecular cell.

[125]  P. Vidalain,et al.  Benchmarking a luciferase complementation assay for detecting protein complexes , 2011, Nature Methods.

[126]  J. Choe,et al.  Human Papillomavirus E2 Down-regulates the Human Telomerase Reverse Transcriptase Promoter* , 2002, The Journal of Biological Chemistry.

[127]  Yong Fang,et al.  Triggering of death receptor apoptotic signaling by human papillomavirus 16 E2 protein in cervical cancer cell lines is mediated by interaction with c-FLIP , 2010, Apoptosis.

[128]  L. Attardi,et al.  Deconstructing p53 transcriptional networks in tumor suppression. , 2012, Trends in cell biology.

[129]  E. Androphy,et al.  Crystal structure of the E2 DNA-binding domain from human papillomavirus type 16: implications for its DNA binding-site selection mechanism. , 1998, Journal of molecular biology.

[130]  S. Boubaker,et al.  Keratinocyte sensitization to tumour necrosis factor-induced nuclear factor kappa B activation by the E2 regulatory protein of human papillomaviruses. , 2011, The Journal of general virology.

[131]  B. Osborne,et al.  Epstein–Barr virus EBNA2 blocks Nur77- mediated apoptosis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[132]  Shwu‐Yuan Wu,et al.  Brd4 links chromatin targeting to HPV transcriptional silencing. , 2006, Genes & development.

[133]  R. Poot,et al.  An ACF1–ISWI chromatin-remodeling complex is required for DNA replication through heterochromatin , 2002, Nature Genetics.

[134]  H. Pfister,et al.  Interaction of Human Papillomavirus 8 Regulatory Proteins E2, E6 and E7 with Components of the TFIID Complex , 1998, Intervirology.

[135]  C. Desaintes,et al.  Control of papillomavirus DNA replication and transcription. , 1996, Seminars in cancer biology.

[136]  Jennifer A. Smith,et al.  Brd4 Regulation of Papillomavirus Protein E2 Stability , 2009, Journal of Virology.

[137]  E. Kipreos,et al.  Cullin-RING ubiquitin ligases: global regulation and activation cycles , 2008, Cell Division.

[138]  H. Pfister,et al.  The Papillomavirus E2 Protein Binds to and Synergizes with C/EBP Factors Involved in Keratinocyte Differentiation , 2003, Journal of Virology.

[139]  K. Yamane,et al.  A Functional Interaction between the Human Papillomavirus 16 Transcription/Replication Factor E2 and the DNA Damage Response Protein TopBP1* , 2002, The Journal of Biological Chemistry.