title: Koilocytosis: a cooperative interaction between the human papillomavirus E5 and E6 oncoproteins.
abstract: A long-recognized, pathognomonic feature of human papillomavirus (HPV) infection is the appearance of halo or koilocytotic cells in the differentiated layers of the squamous epithelium. These koilocytes are squamous epithelial cells that contain an acentric, hyperchromatic nucleus that is displaced by a large perinuclear vacuole. However, the genesis of the cytoplasmic vacuole has remained unclear, particularly because both HPV DNA replication and virion assembly occur exclusively in the nucleus. In clinical biopsies, koilocytosis is observed in both low- and high-risk HPV infections; therefore, in this study, we demonstrated that the E5 and E6 proteins from both low- and high-risk HPVs cooperate to induce koilocyte formation in human cervical cells in vitro, using both stable and transient assays. Both E5 and E6 also induce koilocytosis in human foreskin keratinocytes but not in primate COS cells. Deletion of the 20 C-terminal amino acids of E5 completely abrogates koilocytosis, whereas a 10-amino acid-deletion mutant retains approximately 50% of its activity. Because the E6 protein from both the low- and high-risk HPVs is capable of potentiating koilocytosis with E5, it is apparent that the targeting of both p53 and PDZ proteins by E6 is not involved. Our data suggest new, cooperative functions for both the E5 and E6 proteins, hinting at additional targets and roles for these oncoproteins in the viral life cycle.
authors.affiliation: Department of Pathology, Georgetown University Medical School, 3900 Reservoir Rd. NW, Washington, DC 20057, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Krawczyk
authors.forename: Frank A
authors.initials: FA
authors.lastname: Suprynowicz
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Liu
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Dai
authors.forename: Dan P
authors.initials: DP
authors.lastname: Hartmann
authors.forename: John
authors.initials: J
authors.lastname: Hanover
authors.forename: Richard
authors.initials: R
authors.lastname: Schlegel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D002522:Chlorocebus aethiops; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D005260:Female; D052162:Human papillomavirus 16 / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis*; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D012097:Repressor Proteins / Q000096:biosynthesis*; D000086082:Viroporin Proteins
chemical_list: D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C068651:E6 protein, Human papillomavirus type 16; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins