title: A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes: clues to understanding HPV-pathogenesis in WHIM syndrome.
abstract: The WHIM syndrome, which features high susceptibility to human papillomavirus (HPV) infection, is a rare immunodeficiency associated with autosomal dominant heterozygous mutations of the CXCR4 chemokine receptor. CXCL12 and its receptors, CXCR4 and CXCR7, are linked to tumorigenesis, and we reported that abnormal expression of CXCL12 in epidermal keratinocytes correlates with HPV infection. However, the HPV-related pathologies observed in WHIM patients remain mechanistically unexplained. We show that keratinocytes immortalized by oncogenic HPV16 or HPV18 upregulate CXCL12 and its receptors in a manner dependent upon expression of the viral proteins E6 and E7. Autocrine signaling activated by CXCL12-engagement of its receptors controls motility and survival of the infected cells. Strikingly, expression of a WHIM syndrome-related gain-of-function CXCR4 mutant confers transforming capacity to HPV18-immortalized keratinocytes. These results establish a pivotal role for CXCL12 signaling in HPV-mediated transformation and provide a mechanistic basis for understanding HPV pathogenesis in WHIM syndrome.
authors.affiliation: INSERM U819, Unité Pathogénie Virale, Institut Pasteur, 75724 Paris Cedex 15, France.
authors.forename: Ken Y C
authors.initials: KY
authors.lastname: Chow
authors.forename: Émilie
authors.initials: É
authors.lastname: Brotin
authors.forename: Youcef
authors.initials: Y
authors.lastname: Ben Khalifa
authors.forename: Laetitia
authors.initials: L
authors.lastname: Carthagena
authors.forename: Sébastien
authors.initials: S
authors.lastname: Teissier
authors.forename: Anne
authors.initials: A
authors.lastname: Danckaert
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Galzi
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.forename: Françoise
authors.initials: F
authors.lastname: Thierry
authors.forename: Françoise
authors.initials: F
authors.lastname: Bachelerie
mesh_terms: D000818:Animals; D002465:Cell Movement; D002472:Cell Transformation, Viral; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005260:Female; D052162:Human papillomavirus 16 / Q000502:physiology*; D052161:Human papillomavirus 18 / Q000502:physiology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000473:pathology / Q000821:virology; D007231:Infant, Newborn; D015603:Keratinocytes / Q000821:virology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis; D050725:Papillomavirus E7 Proteins / Q000096:biosynthesis; D030361:Papillomavirus Infections / Q000473:pathology / Q000821:virology*; D000081207:Primary Immunodeficiency Diseases; D054387:Receptors, CXCR / Q000096:biosynthesis* / Q000502:physiology; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis; D014860:Warts / Q000473:pathology / Q000821:virology
chemical_list: D054377:Chemokine CXCL12; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16